Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine mch-1 antagonists, methods of making, and use thereof

ABSTRACT

Novel MCH-1 receptor antagonists are disclosed. These compounds are used in the treatment of various disorders, including obesity, anxiety, depression, non-alcoholic fatty liver disease, and psychiatric disorders. Methods of making these compounds are also described in the present invention.

This application claims benefit of U.S. Provisional Patent ApplicationSer. No. 61/222,447, filed Jul. 1, 2009, and U.S. Provisional PatentApplication Ser. No. 61/329,403, filed Apr. 29, 2010, which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to azinone-substitutedazabicycloalkane-indoles, which are melanin-concentrating hormone(MCH-1) receptor antagonists, pharmaceutical compositions includingthese compounds, and methods of preparation and use thereof. Thecompounds are useful in the treatment of obesity, anxiety, depression,non-alcoholic fatty liver disease, and psychiatric disorders.

BACKGROUND OF THE INVENTION

Obesity and the multitude of co-morbidities associated with obesity suchas diabetes, dyslipidemia, coronary heart disease, and certain cancersare a major concern for public health. The currently availablepharmaceutical therapies for the treatment of obesity have limitedefficacy and side effects that limit their use. Thus, there is asignificant medical need for better pharmacotherapy for obesity.

Obesity has associated with it, economic and social costs. Obese people,an increasing proportion of most western societies, are regarded ashaving out of control feeding habits often associated with lowself-esteem. Moreover, obese persons are more likely to have medicalproblems associated with or exacerbated by the excess body weight.Examples of medical conditions caused, exacerbated, or triggered byexcessive weight include bone fractures, pains in the knee joints,arthritis, increased risk of hypertension, artherosclerosis, stroke, anddiabetes.

Melanin-concentrating hormone (MCH) has been identified as an orexigenicpeptide that exerts an effect on food intake and body weight regulation.MCH is a cyclic 19 amino acid neuropeptide expressed in the zona incertaand lateral hypothalamus in response to both energy restriction andleptin deficiency. MCH is known to stimulate feeding when injected intothe lateral ventricle of rats and the mRNA for MCH is upregulated in thehypothalamus of genetically obese mice (ob/ob) and in fasted control andob/ob animals. In addition, animals treated with MCH show increases inglucose, insulin and leptin levels, mimicking human metabolic syndrome(Gomori, “Chronic Infusion of MCH Causes Obesity in Mice,” Am. J.Physiol. Endocrinol. Metab., 284:E583 (2002)). Mice lacking MCH arehypophagic and lean with increased metabolic rate, whereas animalsover-expressing MCH gain excess weight on both standard and high fatdiets. MCH is thought to have effects on other nervous system functionsas well (Rocksz, “Biological Examination of Melanin ConcentratingHormone 1: Multi-tasking from the Hypothalamus,” Drug News Perspect.,19(5):273 (2006)). An orphan G-protein coupled receptor (GPCR) wasrecently identified as a receptor for MCH. Disruption of the bindingbetween MCH and the MCH receptor, i.e. MCH antagonism, may thus be usedto counteract the effects of MCH (McBriar, “Recent Advances in theDiscovery of Melanin-Concentrating Hormone Receptor Antagonists,” Curr.Opin. Drug Disc. & Dev., 9(4):496 (2006)).

The current preferred treatment for obesity as well as Type IInon-insulin dependent diabetes is diet and exercise with a view towardweight reduction and improved insulin sensitivity for diabetics. Patientcompliance, however, is usually poor. The problem is compounded by thefact that there are currently only two medications approved for thetreatment of obesity (sibutramine (MERIDIA™) and orlistat (XENICALT™)).

The present invention is directed to overcoming these and otherdeficiencies in the art.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I:

whereinR¹ is selected from the group consisting of H, —S(O)_(q)R⁵, —C(O)R⁵,—C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein eachof C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR⁷, —NR⁷R⁸, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁷, or —NR⁷R⁸;R² is independently selected at each location from the group consistingof H, halogen, OR⁴, —NR⁴R⁵, —NR⁴C(O)R⁵, —NR⁴C(O)₂R⁵, —NR⁵C(O)NR⁵R⁶,—S(O)_(q)R⁵, —CN, —C(O)R⁵, —C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl,and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl,and heteroaryl is optionally substituted with from 1 to 3 substituentsindependently selected at each occurrence thereof from C₁-C₃ alkyl,halogen, —CN, —OR⁷, —NR⁷R⁸, and phenyl which is optionally substituted1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN,—OR⁷, or —NR⁷R⁸;R³ is selected from the group consisting of H, halogen, —OR⁴, —NR⁴R⁵,—NR⁴C(O)R⁵, —NR⁴C(O)₂R⁵, —NR⁵C(O)NR⁵R⁶, —S(O)_(q)R⁵, —CN, —C(O)R⁵,—C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein eachof C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR⁷, —NR⁷R⁸, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁷, or —NR⁷R⁸;R⁴ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R⁶, phenyl, or benzyl, whereinphenyl or benzyl is optionally substituted 1 to 3 times with halogen,cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, or benzyl, wherein phenyl orbenzyl is optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁶ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl;R⁷ and R⁸ are each independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R⁶, phenyl,or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to3 times with a substituent selected independently at each occurrencethereof from the group consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄haloalkyl, and C₁-C₄ alkoxy;R⁹ is selected from the group consisting of H, halogen, —OR⁴, —NR⁴R⁵,—NR⁴C(O)R⁵, —NR⁴C(O)₂R⁵, —NR⁵C(O)NR⁵R⁶, —S(O)_(q)R⁵, —CN, —C(O)R⁵,—C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein eachof C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR⁷, —NR⁷R⁸, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁷, or —NR⁷R⁸;

X is CR⁹, C(R⁹)₂, N, or NR⁹; Y is CR⁹, C, or N; Z is C, CH, or N;

L is —(CH₂)_(p)—O—, —(CH₂)_(p)—, —CH═CH—, or a bond;B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of thearyl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substitutedwith from 1 to 3 substituents selected from the group consisting of H,alkoxy, —S-alkyl, optionally substituted C₁-C₆ alkyl, halogen, —CF₃, and—CN;n is 1 or 2;m is 0, 1, 2, or 3;p is from 1 to 4;q is from 0 to 2; and

represents an optional double bond,or an oxide thereof, a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.

Additional aspects of the present invention include pharmaceuticalcompositions comprising a compound of the invention and apharmaceutically acceptable carrier and, optionally, one or moreadditional additive agent(s) as discussed below.

The present invention also relates to a method of treating a disease orcondition which is susceptible to treatment with a MCH-1 receptorantagonist. This method involves selecting a patient with a disease orcondition which is susceptible to treatment with a MCH-1 antagonist andadministering to the patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a method of treatingobesity in a subject in need of weight loss. This method involvesselecting a patient in need of weight loss and administering to thepatient a therapeutically effective amount of a compound of formula I ora pharmaceutically acceptable salt thereof.

Yet another aspect of the present invention relates to a method oftreating obesity in a subject who has experienced weight loss. Thismethod involves selecting a patient who has experienced weight loss andadministering to the patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

A further aspect of the present invention relates to a method oftreating anxiety. This method involves selecting a patient with anxietyand administering to the patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating depression.This method involves selecting a patient with depression andadministering to the patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a method of treatingnon-alcoholic fatty liver disease. This method involves selecting apatient who has non-alcoholic fatty liver disease and administering tothe patient a therapeutically effective amount of a compound of formulaI or a pharmaceutically acceptable salt thereof.

A further aspect of the present invention relates to a process forpreparation of a product compound of formula I which includes treating afirst intermediate of formula II:

wherein Q is a halogen, under conditions effective to form the compoundof formula (I).

It has now been found that compounds of formula I are MCH-1 receptorantagonists. This invention provides compounds that bind to the MCH-1receptor with high affinity. The compounds provided by formula I areuseful for the treatment of obesity, anxiety, depression, psychiatricdisorders, and other disorders described herein. In particular, it iscontemplated that the compounds of this invention will be effective intreating obesity, including weight loss and maintenance of weight lossin patients who have been diagnosed with obesity by the one or more ofthe following measurements: an increased body mass index, increasedwaist circumference (an indicator of intra-abdominal fat), Dual EnergyX-Ray Absorptiometry (DEXA), and truncal (android) fat mass. It isfurther contemplated that the compounds of the invention will beeffective in inducing improvements in certain factors measured in thesetests.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of formula I:

whereinR¹ is selected from the group consisting of H, —S(O)_(q)R⁵, —C(O)R⁵,—C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein eachof C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR⁷, —NR⁷R⁸, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁷, or —NR⁷R⁸;R² is independently selected at each location from the group consistingof H, halogen, —OR⁴, —NR⁴R⁵, —NR⁴C(O)R⁵, —NR⁴C(O)₂R⁵, —NR⁵C(O)NR⁵R⁶,—S(O)_(q)R⁵, —CN, —C(O)R⁵, —C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl,and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl,and heteroaryl is optionally substituted with from 1 to 3 substituentsindependently selected at each occurrence thereof from C₁-C₃ alkyl,halogen, —CN, —OR⁷, —NR⁷R⁸, and phenyl which is optionally substituted1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN,—OR⁷, or —NR⁷R⁸;R³ is selected from the group consisting of H, halogen, —OR⁴, —NR⁴R⁵,—NR⁴C(O)R⁵, —NR⁴C(O)₂R⁵, —NR⁵C(O)NR⁵R⁶, —S(O)_(q)R⁵, —CN, —C(O)R⁵,—C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein eachof C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR⁷, —NR⁷R⁸, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁷, or —NR⁷R⁸;R⁴ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R⁶, phenyl, or benzyl, whereinphenyl or benzyl is optionally substituted 1 to 3 times with halogen,cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, or benzyl, wherein phenyl orbenzyl is optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁶ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl;R⁷ and R⁸ are each independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R⁶, phenyl,or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to3 times with a substituent selected independently at each occurrencethereof from the group consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄haloalkyl, and C₁-C₄ alkoxy;R⁹ is selected from the group consisting of H, halogen, —OR⁴, —NR⁴R⁵,—NR⁴C(O)R⁵, —NR⁴C(O)₂R⁵, —NR⁵C(O)NR⁵R⁶, —S(O)_(q)R⁵, —CN, —C(O)R⁵,—C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein eachof C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR⁷, —NR⁷R⁸, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁷, or —NR⁷R⁸;

X is CR⁹, C(R⁹)₂, N, or NR⁹; Y is CR⁹, C, or N; Z is C, CH, or N;

L is —(CH₂)_(p)—O—, —(CH₂)_(p)—, —CH═CH—, or a bond;B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of thearyl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substitutedwith from 1 to 3 substituents selected from the group consisting of H,alkoxy, —S-alkyl, optionally substituted C₁-C₆ alkyl, halogen, —CF₃, and—CN;n is 1 or 2;m is 0, 1, 2, or 3;p is from 1 to 4;q is from 0 to 2; and

represents an optional double bond,or an oxide thereof, a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings If not defined otherwise herein, all technicaland scientific terms used herein have the same meaning as is commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. In the event that there is a plurality of definitions for aterm herein, those in this section prevail unless stated otherwise.

The term “alkyl” means an aliphatic hydrocarbon group which may bestraight or branched. When not otherwise restricted, the term refers toan alkyl of 20 or fewer carbons. Lower alkyl refers to alkyl groupshaving about 1 to about 6 carbon atoms in the chain. Branched means thatone or more lower alkyl groups such as methyl, ethyl or propyl areattached to a linear alkyl chain. Exemplary alkyl groups include methyl,ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, and thelike.

The term “alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Preferred alkenyl groupshave 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl, or propyl are attached toa linear alkenyl chain. Exemplary alkenyl groups include ethenyl,propenyl, n-butenyl, and i-butenyl. In the present invention, the term“alkenyl” may also refer to a hydrocarbon chain having 2 to 6 carbonscontaining at least one double bond and at least one triple bond.

The term “alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Preferred alkynyl groupshave 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl, or propyl are attached toa linear alkynyl chain. Exemplary alkynyl groups include ethynyl,propynyl, n-butynyl, 2-butyryl, 3-methylbutynyl, and n-pentynyl.

The term “aryl” means an aromatic monocyclic or multi-cyclic(polycyclic) ring system of 6 to about 19 carbon atoms, preferably of 6to about 10 carbon atoms, and includes arylalkyl groups. The ring systemof the aryl group may be optionally substituted. Representative arylgroups of the present invention include, but are not limited to, groupssuch as phenyl, naphthyl, azulenyl, phenanthrenyl, anthracenyl,fluorenyl, pyrenyl, triphenylenyl, chrysenyl, and naphthacenyl.

The term “arylalkyl” means an alkyl residue attached to an aryl ring.Examples are benzyl, phenethyl, and the like.

The term “alkoxy” means groups of from 1 to 8 carbon atoms of astraight, branched, or cyclic configuration and combinations thereofattached to the parent structure through an oxygen. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, andthe like. Lower-alkoxy refers to groups containing one to four carbons.For the purposes of the present patent application, alkoxy also includesmethylenedioxy and ethylenedioxy in which each oxygen atom is bonded tothe atom, chain, or ring from which the methylenedioxy or ethylenedioxygroup is pendant so as to form a ring. Thus, for example, phenylsubstituted by alkoxy may be, for example,

The term “compounds of the invention”, and equivalent expressions, aremeant to embrace compounds of general formula I as hereinbeforedescribed, which expression includes the prodrugs, the pharmaceuticallyacceptable salts, the oxides, the solvates, e.g. hydrates, and inclusioncomplexes of that compound, where the context so permits, as well as anystereoisomeric form, or a mixture of any such forms of that compound inany ratio. Inclusion complexes are described in Remington, The Scienceand Practice of Pharmacy, 19th Ed. 1:176-177 (1995), which is herebyincorporated by reference in its entirety. The most commonly employedinclusion complexes are those with cyclodextrins, and all cyclodextrincomplexes, natural and synthetic, are specifically encompassed withinthe claims. Thus, in accordance with some embodiments of the invention,a compound as described herein, including in the contexts ofpharmaceutical compositions, methods of treatment, and compounds per se,is provided as the salt form. Similarly, reference to intermediates,whether or not they themselves are claimed, is meant to embrace theirsalts, and solvates, where the context so permits. For the sake ofclarity, particular instances when the context so permits are sometimesindicated in the text, but these instances are purely illustrative andit is not intended to exclude other instances when the context sopermits.

The term “cycloalkyl” means a non-aromatic, saturated or unsaturated,mono- or multi-cyclic ring system of about 3 to about 7 carbon atoms,preferably of about 5 to about 7 carbon atoms, and which may include atleast one double bond. Exemplary cycloalkyl groups include, withoutlimitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclophenyl,anti-bicyclopropane, and syn-tricyclopropane.

The term “cycloalkylalkyl” means an cycloalkyl-alkyl-group in which thecycloalkyl and alkyl are as defined herein. Exemplary cycloalkylalkylgroups include cyclopropylmethyl and cyclopentylmethyl. The alkylradical and the cycloalkyl radical may be optionally substituted asdefined above.

The term “haloalkyl” means both branched and straight-chain alkylsubstituted with one or more halogen, wherein the alkyl group is asherein described.

The term “halogen” means fluorine, chlorine, bromine, or iodine.

The term “heteroaryl” means an aromatic monocyclic or multi-cyclic ringsystem of about 5 to about 19 ring atoms, preferably about 5 to about 10ring atoms, in which one or more of the atoms in the ring system is/areelement(s) other than carbon, for example, nitrogen, oxygen, or sulfur.In the case of multi-cyclic ring system, only one of the rings needs tobe aromatic for the ring system to be defined as “heteroaryl”. Preferredheteroaryls contain about 5 to 6 ring atoms. The prefix aza, oxa, thia,or thio before heteroaryl means that at least a nitrogen, oxygen, orsulfur atom, respectively, is present as a ring atom. A nitrogen,carbon, or sulfur atom in the heteroaryl ring may be optionallyoxidized; the nitrogen may optionally be quaternized. Representativeheteroaryls include pyridyl, 2-oxo-pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, isoindolyl,benzofuranyl, benzothiophenyl, indolinyl, 2-oxoindolinyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl,benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl,benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl,quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl,benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl,6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl,imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,[1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl,thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl,furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-c]pyrimidinyl,furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl,5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl,6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl,2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl,benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,[1,2,4]triazolo[4,3-a]pyrazinyl,3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, and the like.

As used herein, “heterocyclyl” or “heterocycle” refers to a stable 3- to18-membered ring (radical) which consists of carbon atoms and from oneto five heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur. For purposes of this invention, the heterocycle maybe a monocyclic, or a polycyclic ring system, which may include fused,bridged, or spiro ring systems; and the nitrogen, carbon, or sulfuratoms in the heterocycle may be optionally oxidized; the nitrogen atommay be optionally quaternized; and the ring radical may be partially orfully saturated. Examples of such heterocycles include, withoutlimitation, azepinyl, azocanyl, pyranyl dioxanyl, dithianyl,1,3-dioxolanyl, tetrahydrofuryl, dihydropyrrolidinyl,decahydroisoquinolyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, oxazolidinyl,oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl,pyrazolidinyl, thiazolidinyl, tetrahydropyranyl, thiamorpholinyl,thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. Furtherheterocycles and heteroaryls are described in Katritzky et al., eds.,Comprehensive Heterocyclic Chemistry: The Structure, Reactions,Synthesis and Use of Heterocyclic Compounds, Vol. 1-8, Pergamon Press,N.Y. (1984), which is hereby incorporated by reference in its entirety.

The term “method of treating” means amelioration or relief from thesymptoms and/or effects associated with the disorders described herein.As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis.

The term “monocyclic” used herein indicates a molecular structure havingone ring.

The term “optionally substituted” is used to indicate that a group mayhave a substituent at each substitutable atom of the group (includingmore than one substituent on a single atom), provided that thedesignated atom's normal valency is not exceeded and the identity ofeach substituent is independent of the others. In accordance with thepresent invention, up to three H atoms in each residue are replaced withalkyl, halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy(also referred to as alkoxycarbonyl), carboxamido (also referred to asalkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino,dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino,amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, orheteroaryloxy. “Unsubstituted” atoms bear all of the hydrogen atomsdictated by their valency. When a substituent is keto (i.e., =0), thentwo hydrogens on the atom are replaced. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds; by “stable compound” or “stable structure” is meant acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

The term “pharmaceutical composition” means a composition comprising acompound of formula I and at least one component comprisingpharmaceutically acceptable carriers, diluents, adjuvants, excipients,or vehicles, such as preserving agents, fillers, disintegrating agents,wetting agents, emulsifying agents, suspending agents, sweeteningagents, flavoring agents, perfuming agents, antibacterial agents,antifungal agents, lubricating agents, and dispensing agents, dependingon the nature of the mode of administration and dosage forms. As usedherein, the term “pharmaceutically acceptable carrier” is used to meanany carrier, diluent, adjuvant, excipient, or vehicle, as describedherein. Examples of suspending agents include ethoxylated isostearylalcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,or mixtures of these substances. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monosterate andgelatin. Examples of suitable carriers, diluents, solvents, or vehiclesinclude water, ethanol, polyols, suitable mixtures thereof, vegetableoils (such as olive oil), and injectable organic esters such as ethyloleate. Examples of excipients include lactose, milk sugar, sodiumcitrate, calcium carbonate, and dicalcium phosphate. Examples ofdisintegrating agents include starch, alginic acids, and certain complexsilicates. Examples of lubricants include magnesium stearate, sodiumlauryl sulphate, talc, as well as high molecular weight polyethyleneglycols.

The term “pharmaceutically acceptable” means it is, within the scope ofsound medical judgment, suitable for use in contact with the cells ofhumans and lower animals without undue toxicity, irritation, allergicresponse and the like, and are commensurate with a reasonablebenefit/risk ratio.

The term “pharmaceutically acceptable dosage forms” means dosage formsof the compound of the invention, and includes, for example, tablets,dragees, powders, elixirs, syrups, liquid preparations, includingsuspensions, sprays, inhalants tablets, lozenges, emulsions, solutions,granules, capsules, and suppositories, as well as liquid preparationsfor injections, including liposome preparations. Techniques andformulations generally may be found in Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa., latest edition, which ishereby incorporated by reference in its entirety.

The term “pharmaceutically acceptable prodrugs” as used herein meansthose prodrugs of the compounds useful according to the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “prodrug” means compoundsthat are rapidly transformed in vivo to yield the parent compound of theabove formula, for example by hydrolysis in blood. Commonly, theconversion of prodrug to drug occurs by enzymatic processes in the liveror blood of the mammal. Many of the compounds of the invention may bechemically modified without absorption into the systemic circulation,and in those cases, activation in vivo may come about by chemical action(as in the acid-catalyzed cleavage in the stomach) or through theintermediacy of enzymes and microflora in the gastrointestinal GI tract.Functional groups which may be rapidly transformed, by metaboliccleavage, in vivo form a class of groups reactive with the carboxylgroup of the compounds of this invention. They include, but are notlimited to, such groups as alkanoyl (such as acetyl, propionyl, butyryl,and the like), unsubstituted and substituted aroyl (such as benzoyl andsubstituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl),trialkylsilyl (such as trimethyl- and triethysilyl), monoesters formedwith dicarboxylic acids (such as succinyl), and the like. Because of theease with which the metabolically cleavable groups of the compoundsuseful according to this invention are cleaved in vivo, the compoundsbearing such groups act as pro-drugs. The compounds bearing themetabolically cleavable groups have the advantage that they may exhibitimproved bioavailability as a result of enhanced solubility and/or rateof absorption conferred upon the parent compound by virtue of thepresence of the metabolically cleavable group. A thorough discussion ofprodrugs is provided in the following: Design of Prodrugs, H. Bundgaard,ed., Elsevier (1985); Methods in Enzymology, K. Widder et al, Ed.,Academic Press, 42, p. 309-396 (1985); A Textbook of Drug Design andDevelopment, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; “Designand Applications of Prodrugs,” p. 113-191 (1991); Advanced Drug DeliveryReviews, H. Bundgaard, 8, p. 1-38 (1992); Journal of PharmaceuticalSciences, 77:285 (1988); Nakeya et al, Chem. Pharm. Bull., 32:692(1984); Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and Bioreversible Carriers in DrugDesign, Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press (1987), which are incorporated herein by reference intheir entirety. Examples of prodrugs include, but are not limited to,acetate, formate, and benzoate derivatives of alcohol and aminefunctional groups in the compounds of the invention.

The term “pharmaceutically acceptable salt” refers to salts preparedfrom pharmaceutically acceptable non-toxic acids or bases includinginorganic acids and bases and organic acids and bases. Suitablepharmaceutically acceptable acid addition salts for the compounds of thepresent invention include acetic, benzenesulfonic (besylate), benzoic,camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like.Suitable pharmaceutically acceptable base addition salts for thecompounds of the present invention include metallic salts made fromaluminum, calcium, lithium, magnesium, potassium, sodium and zinc ororganic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine. Pharmaceutically acceptable saltsfurther include, but are not limited to, amine salts, such as but notlimited to N,N′ dibenzylethylenediamine, chloroprocaine, choline,ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl- benzimidazole,diethylamine and other alkylamines, piperazine, and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limitedto lithium, potassium, and sodium; alkali earth metal salts, such as butnot limited to barium, calcium, and magnesium; transition metal salts,such as but not limited to zinc; and other metal salts, such as but notlimited to sodium hydrogen phosphate and disodium phosphate; and alsoincluding, but not limited to, salts of mineral acids, such as but notlimited to hydrochlorides and sulfates; and salts of organic acids, suchas but not limited to acetates, lactates, malates, tartrates, citrates,ascorbates, succinates, butyrates, valerates, and fumarates.Pharmaceutically acceptable esters include, but are not limited to,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclylesters of acidic groups, including, but not limited to, carboxylicacids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinicacids, and boronic acids. Pharmaceutical acceptable enol ethers include,but are not limited to, derivatives of formula C═C(OR) where R ishydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, orheterocyclyl. Pharmaceutically acceptable enol esters include, but arenot limited to, derivatives of formula C═C(OC(O)R) where R is hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl.Pharmaceutical acceptable solvates and hydrates are complexes of acompound with one or more solvent or water molecules, or 1 to about 100,or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.

The term “polycyclic” or “multi-cyclic” used herein indicates amolecular structure having two or more rings, including, but not limitedto, fused, bridged, or spiro rings.

Terminology related to “protecting”, “deprotecting,” and “protected”functionalities occurs throughout this application. Such terminology iswell understood by persons of skill in the art and is used in thecontext of processes which involve sequential treatment with a series ofreagents. In that context, a protecting group refers to a group which isused to mask a functionality during a process step in which it wouldotherwise react, but in which reaction is undesirable. The protectinggroup prevents reaction at that step, but may be subsequently removed toexpose the original functionality. The removal or “deprotection” occursafter the completion of the reaction or reactions in which thefunctionality would interfere. Thus, when a sequence of reagents isspecified, as it is in the processes of the invention, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups.” Suitable groups for that purpose are discussedin standard textbooks in the field of chemistry, such as Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York(1991), which is hereby incorporated by reference in its entirety.

The term “solvate” refers to a compound of formula I in the solid state,wherein molecules of a suitable solvent are incorporated in the crystallattice. A suitable solvent for therapeutic administration isphysiologically tolerable at the dosage administered. Examples ofsuitable solvents for therapeutic administration are ethanol and water.When water is the solvent, the solvate is referred to as a hydrate. Ingeneral, solvates are formed by dissolving the compound in theappropriate solvent and isolating the solvate by cooling or using anantisolvent. The solvate is typically dried or azeotroped under ambientconditions.

The term “therapeutically effective amount” is meant to describe anamount of compound of the present invention effective producing thedesired therapeutic effect. Such amounts generally vary according to anumber of factors well within the purview of ordinarily skilled artisansgiven the description provided herein to determine and account for.These include, without limitation: the particular subject, as well asits age, weight, height, general physical condition, and medicalhistory, the particular compound used, as well as the carrier in whichit is formulated and the route of administration selected for it; and,the nature and severity of the condition being treated.

Compounds described herein may contain one or more asymmetric centersand may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. Each chiral center may be defined, in terms ofabsolute stereochemistry, as (R)- or (S)-. The present invention ismeant to include all such possible isomers, as well as mixtures thereof,including racemic and optically pure forms. Optically active (R)- and(S)-, (−)- and (+)-, or (D)- and (L)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. Likewise, all tautomeric forms are also intended tobe included.

This invention also envisions the “quaternization” of any basicnitrogen-containing groups of the compounds disclosed herein. The basicnitrogen can be quaternized with any agents known to those of ordinaryskill in the art including, for example, lower alkyl halides, such asmethyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkylsulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; and aralkyl halides including benzyl and phenethylbromides. Water or oil-soluble or dispersible products may be obtainedby such quaternization.

In the characterization of some of the substituents, it is recited thatcertain substituents may combine to form rings. Unless stated otherwise,it is intended that such rings may exhibit various degrees ofunsaturation (from fully saturated to fully unsaturated), may includeheteroatoms, and may be substituted with lower alkyl or alkoxy.

In accordance with one embodiment of the present invention, R¹ is H.

In accordance with another embodiment of the present invention, R¹ isC₁-C₆ alkyl, for example, methyl.

In accordance with one embodiment of the present invention, R² is H,halogen, or optionally C₁-C₆ alkyl. In yet another embodiment R³ is H,halogen, or optionally C₁-C₆ alkyl.

In accordance with another embodiment of the present invention, thecompound of formula (I) has the structure:

In accordance with one embodiment of the present invention, the compoundof formula (I) has the structure:

In accordance with one embodiment of the present invention, the compoundof formula (I) has the structure:

In accordance with one embodiment of the present invention, X is CH.

In accordance with one embodiment of the present invention, X is N.

In accordance with one embodiment of the present invention, L is a bond.In accordance with another embodiment of the present invention, L is—CH₂—O—.

In accordance with one embodiment of the present invention, B is aryl.In one preferred embodiment, B is phenyl. In accordance with anotherembodiment of the present invention, B is heteroaryl. In one preferredembodiment, B is pyridinyl, for example pyridin-2-yl or pyridin-3-yl,pyridazinyl, for example, pyridazin-3-yl, or pyrimidinyl, for example,pyrimidin-5-yl.

As described herein, B may be optionally substituted. In one preferredembodiment, B is unsubstituted. In another preferred embodiment, B issubstituted with one substituent selected from trifluoromethyl andfluoro. In yet another preferred embodiment, B is selected from phenyl,5-(trifluoromethyl)pyridin-2-yl, 5-fluoropyridin-2-yl,6-(trifluoromethyl)pyridin-3-yl, 6-(trifluoromethyl)pyridazin-3-yl,2,4-difluorophenyl, and 4-(trifluoromethyl)phenyl.

Within these embodiments, the selection of a particular preferredsubstituent at any one of R¹-R⁹, X, Y, Z, L, and B does not affect theselection of a substituent at any of the others of R¹-R⁹, X, Y, Z, L,and B. That is, preferred compounds provided herein have any of thepreferred substituents at any of the positions.

In accordance with one embodiment of the present invention, the compoundis selected from

In accordance with one embodiment of the present invention, the compoundis selected from

In accordance with another embodiment of the present invention, thecompound is selected from

Tables 1 and 2, infra, list compounds representative of embodiments ofthe present invention.

One embodiment of the present invention relates to pharmaceuticallyacceptable salts, or non-salt forms, of any of the compounds of formulaI described herein. In one embodiment, the salt is an HCl salt.

Single enantiomers, any mixture of enantiomers, including racemicmixtures, or diastereomers (both separated and as any mixtures) of thecompounds of the present invention are also included within the scope ofthe invention.

The scope of the present invention also encompasses active metabolitesof the present compounds.

The present invention also includes compounds of formula I, wherein oneor more of the atoms, e.g., C or H, are replaced by the correspondingradioactive isotopes of that atom (e.g., C replaced by ¹⁴C and Hreplaced by ³H), or a stable isotope of that atom (e.g., C replaced by¹³C or H replaced by ²H). Radioisotopes of hydrogen, carbon,phosphorous, fluorine, iodine and chlorine include ³H, ¹⁴C, ³⁵S, ¹⁸F,³²P, ³³P, ¹²⁵I, and ³⁶Cl, respectively. Compounds that contain thoseradioisotopes and/or other radioisotopes of other atoms are within thescope of this invention. Radiolabeled compounds described herein andprodrugs thereof can generally be prepared by methods well known tothose skilled in the art. Conveniently, such radiolabeled compounds canbe prepared by carrying out the procedures disclosed in the Examples andSchemes by substituting a readily available radiolabeled reagent for anon-radiolabeled reagent. Such compounds have a variety of potentialuses, e.g., as standards and reagents in determining the binding abilityof a potential pharmaceutical. In addition, in the case of stableisotopes, such compounds may have the potential to favorably modify thebiological properties, e.g., pharmacological and/or pharmacokineticproperties, of compounds of formula I. The details concerning selectionof suitable sites for incorporating radioactive isotopes into thecompounds are known to those skilled in the art.

Compounds of the present invention as described herein are useful asMCH-1 receptor antagonists. It may be found upon examination thatcompounds that are not presently excluded from the claims are notpatentable to the inventors in this application. In that case, theexclusion of species and genera in applicants' claims are to beconsidered artifacts of patent prosecution and not reflective of theinventors' concept or description of their invention. The invention, ina compound aspect, is all compounds of formula I, except those that arein the public's possession.

While it may be possible for compounds of formula Ito be administered asthe raw chemical, it will often be preferable to present them as part ofa pharmaceutical composition. Accordingly, another aspect of the presentinvention is a pharmaceutical composition containing a therapeuticallyeffective amount of a compound of formula I, or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier. The carrier must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. Furthermore, when reference ismade in an independent claim to a compound or a pharmaceuticallyacceptable salt thereof, it will be understood that claims which dependfrom that independent claim which refer to such a compound also includepharmaceutically acceptable salts of the compound, even if explicitreference is not made to the salts.

Solid carriers suitable for use in the composition of the inventioninclude one or more substances which may also act as flavoring agents,lubricants, solubilizers, suspending agents, fillers, glidants,compression aides, binders, tablet-disintegrating agents, orencapsulating materials. In powders, the carrier may be a finely dividedsolid which is in admixture with a finely divided compound of formula I.In tablets, the formula I compound may be mixed with a carrier havingthe necessary compression properties in suitable proportions andcompacted in the shape and size desired. Said powders and tablets maycontain up to 99% by weight of the formula I compound. Solid carrierssuitable for use in the composition of the invention include calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes, and ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparingsolutions, suspensions, emulsions, syrups and elixirs may be employed inthe composition of the invention. Compounds of formula I may bedissolved or suspended in a pharmaceutically acceptable liquid carriersuch as water, an organic solvent, or a pharmaceutically acceptable oilor fat, or a mixture thereof. Said liquid composition may contain othersuitable pharmaceutical additives such as solubilizers, emulsifiers,buffers, preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, coloring agents, viscosity regulators, stabilizers,osmo-regulators, or the like. Examples of liquid carriers suitable fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) or their derivatives,or oils (e.g., fractionated coconut oil and arachis oil). For parenteraladministration the carrier may also be an oily ester such as ethyloleate or isopropyl myristate.

In one embodiment of the present invention, the pharmaceuticalcomposition further comprises one or more other therapeutic adjuncts,e.g., other compounds effective in the treatment of obesity, anxiety,depression, or non-alcoholic fatty liver disease, that are known topersons of skill in the art. Such other therapeutic adjunts aredescribed below.

Another aspect of the present invention relates to a method of treatinga disease or condition which is susceptible to treatment with an MCH-1receptor antagonist. This method involves selecting a patient with adisease or condition which is susceptible to treatment with an MCH-1receptor antagonist and administering to the patient a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable salt thereof.

Diseases or conditions which are susceptible to treatment with an MCH-1receptor antagonist in accordance with the present invention include,but are not limited to, obesity, general anxiety disorders, socialphobias, vertigo, obsessive-compulsive disorders, panic disorders,post-traumatic stress disorders, Parkinson's Disease Psychosis,schizophrenia, cognitive decline and defects in schizophrenia, preseniledementias, Alzheimer's Disease, psychological disorders, depression,substance abuse disorders, dementia associated with neurodegenerativedisease, cognition deficits, and epilepsy (see PCT Publication No. WO2007/010275, which is hereby incorporated by reference in its entirety).

As described above, the compounds of the present invention are useful asMCH-1 antagonists. As used in this invention, the term “antagonist”refers to a compound which binds to, and decreases the activity of, areceptor in the presence of an agonist. In the case of a G-proteincoupled receptor, activation may be measured using any appropriatesecond messenger system which is coupled to the receptor in a cell ortissue in which the receptor is expressed. Some specific, but by nomeans limiting, examples of well-known second messenger systems areadenylate cyclase, intracellular calcium mobilization, ion channelactivation, guanylate cyclase, and inositol phospholipid hydrolysis.

As used herein, treatment means any manner in which one or more of thesymptoms of a disease or disorder are ameliorated or otherwisebeneficially altered. Treatment also encompasses any pharmaceutical useof the compositions herein, such as use for treating diseases ordisorders in which MCH-1 receptor activity is implicated.

In another embodiment of the present invention, the above method furtherinvolves administering a therapeutically effective amount of one or moretherapeutic adjuncts. Suitable therapeutic adjuncts include, but are notlimited to, anti-obesity and/or anorectic agents, anti-anxiety agents,anti-depression agents, and anti-non-alcoholic fatty liver diseaseagents.

Suitable anti-obesity and/or anorectic adjuncts include, but are notlimited to, phenylpropanolamine, ephedrine, pseudoephedrine,phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A)agonist, a monoamine reuptake inhibitor (such as sibutramine), asympathomimetic agent, a serotonergic agent (such as dexfenfluramine orfenfluramine), a dopamine agonist (such as bromocriptine), amelanocyte-stimulating hormone receptor agonist or mimetic, amelanocyte-stimulating hormone analog, a cannabinoid receptor antagonistor inverse agonist, a melanin concentrating hormone receptor antagonist,a serotonin 5-HT₆ receptor antagonist, a serotonin 5-HT_(2C) receptoragonist, the OB protein (hereinafter referred to as “leptin”), a leptinanalog, a leptin receptor agonist, the amylin peptide, an amylin analog,an amylin receptor agonist, a neuropeptide Y receptor modulator, agalanin antagonist, or a GI lipase inhibitor or decreaser (such asorlistat). Other anorectic agents include bombesin agonists,dehydroepiandrosterone or analogs thereof, glucocorticoid receptoragonists and antagonists, orexin receptor antagonists, urocortin bindingprotein antagonists, agonists of the glucagon-like peptide-1 receptorsuch as Exendin and ciliary neurotrophic factors such as Axokine

Suitable anti-anxiety adjunts include, but are not limited to, anallosteric modulator of the GABA_(A) receptor (such as diazepam,lorazepam, or alprazolam), a serotonin 5-HT_(1A) receptor partialagonist (such as buspirone), a selective serotonin reuptake inhibitor(SSRI, such as citalopram, escitalopram, fluoxetine, paroxetine, orsertraline), a serotonin-norepinephrine reuptake inhibitor (SNRI, suchas duloxetine or venlafaxine), a monoamine neurotransmitter reuptakeinhibitor of the tricyclic antidepressant (TCA) class (such asamitriptyline, desipramine, or imipramine), a combined serotoninreuptake inhibitor and 5-HT_(2C) antagonist (such as trazodone), and anH₁ receptor antagonist (such as hydroxyzine).

Suitable anti-depression adjuncts include, but are not limited to, aserotonin 5-HT_(1A) receptor partial agonist (such as buspirone), aselective serotonin reuptake inhibitor (SSRI, such as citalopram,escitalopram, fluoxetine, paroxetine, or sertraline), aserotonin-norepinephrine reuptake inhibitor (SNRI, such as duloxetine orvenlafaxine), a monoamine neurotransmitter reuptake inhibitor of thetricyclic antidepressant (TCA) class (such as amitriptyline,desipramine, or imipramine), a combined serotonin reuptake inhibitor and5-HT_(2C) antagonist (such as trazodone), a noradrenergic and specificserotonergic antidepressant (NaSSA, such as mianserin or mirtazapine), anorepinephrine reuptake inhibitor (NRI, such as atomoxetine orMazindol), a norepinephrine-dopamine reuptake inhibitor (NDRI, such asbupropion), and a monoamine oxidase inhibitor (MAOI, such asisocarboxazid or moclobemide).

Suitable anti-non-alcoholic fatty liver disease adjuncts include, butare not limited to, an AMP-activated protein kinase (AMPK) agonist (suchas metformin), a peroxisome proliferator-activated receptor (PPAR) gammaactivator (such as rosiglitazone, pioglitazone, or troglitazone), aHMG-CoA reductase inhibitor (such as atorvastatin or simvastatin), and aPDE4 inhibitor (such as pentoxifylline).

In one embodiment, the patient is a mammal. The term “mammal” is used inits dictionary sense. The term “mammal” includes, for example, mice,hamsters, rats, cows, sheep, pigs, goats, and horses, monkeys, dogs(e.g., Canis familiaris), cats, rabbits, guinea pigs, and primates,including humans.

The present invention also relates to a method of treating obesity in asubject in need of weight loss. This method involves selecting a patientin need of weight loss and administering to the patient atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt thereof.

This method further involves administering an anti-obesity adjunct, asdescribed above.

Yet another aspect of the present invention relates to a method oftreating obesity in a subject who has experienced weight loss. Thismethod involves selecting a patient who has experienced weight loss andadministering to the patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

A further aspect of the present invention relates to a method oftreating anxiety. This method involves selecting a patient with anxietyand administering to the patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

This method further involves administering an anti-anxiety adjunct, asdescribed above.

The present invention also relates to a method of treating depression.This method involves selecting a patient with depression andadministering to the patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

This method further involves administering an anti-depression adjunct,as described above.

Another aspect of the present invention relates to a method of treatingnon-alcoholic fatty liver disease. This method involves selecting apatient who has non-alcoholic fatty liver disease and administering tothe patient a therapeutically effective amount of a compound of formulaI or a pharmaceutically acceptable salt thereof.

This method further involves administering an anti-non-alcoholic fattyliver disease adjunct, as described above.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

Another aspect of the present invention relates to a process ofpreparing a product compound of formula I:

This process involves treating a first intermediate of formula II:

wherein Q is a halogen, under conditions effective to form the productcompound of formula (I), wherein R¹-R⁹, X, Y, Z, L and B are as definedabove.

In one embodiment, treating comprises reacting the first intermediatewith a second intermediate having the structure:

In another embodiment, the method further involves reacting a compoundof formula III:

with a compound of formula IV:

under conditions effective to produce the first intermediate compound.

Compounds useful according to the invention may be prepared by theapplication or adaptation of known methods, by which is meant methodsused heretofore or described in the literature, for example, thosedescribed by Larock, Comprehensive Organic Transformations, Wiley-VCHpublishers, New York (1989), which is hereby incorporated by referencein its entirety.

A compound of formula I including a group containing one or morenitrogen ring atoms, may be converted to the corresponding compoundwherein one or more nitrogen ring atom of the group is oxidized to anN-oxide, preferably by reacting with a peracid, for example peraceticacid in acetic acid or m-chloroperoxybenzoic acid in an inert solventsuch as dichloromethane, at a temperature from about room temperature toreflux, preferably at elevated temperature.

In the reactions described hereinafter, it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio, orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice and as describedabove.

The novel MCH-1 antagonists of formula I of this invention can beprepared by the methods illustrated in the general reaction schemes as,for example, described below, or by modifications thereof, using readilyavailable starting materials, reagents, and conventional synthesisprocedures. In these reactions, it is also possible to make use ofvariants that are known in the art but are not mentioned here. Althoughthe syntheses depicted herein may result in the preparation ofenantiomers having a particular stereochemistry, included within thescope of the present invention are compounds of formula I in anystereoisomeric form, and preparation of compounds of formula I instereoisomeric forms other than those depicted herein would be obviousto one of ordinary skill in the chemical arts based on the procedurespresented herein.

Synthetic Methods

Compounds of formula 1 (or a salt thereof, wherein R¹ is H or alkyl andZ is CH or N) can be treated with compounds of formula 2 (wherein n is 1or 2) under heated acidic conditions to provide compounds of formula 3(wherein R¹ is H or alkyl, Z is CH or N, and n is 1 or 2). In the casewhere R¹ is H, optional alkylation or protection of compound 3 canprovide compounds of formula 3 wherein R¹ is alkyl or a protecting groupsuch as tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl.

Compounds of formula 7 (wherein B is aryl, heteroaryl, heterocyclyl, orcycloalkyl; R¹⁰, R¹¹, and R¹² are each independently selected from H,alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; and X is CH) can beprepared by treating compounds of formula 4 (wherein X¹ is chlorine,bromine or iodine and X is CH) with compounds of formula 5 (wherein B isaryl, heteroaryl, heterocyclyl, or cycloalkyl; R¹⁰, R¹¹, and R¹² areeach independently selected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃,and —CN; Z¹ is —B(OH)₂, —B(OR¹³)₂, —SnR¹³ ₃ or the like and R¹³ isalkyl), a catalyst such as palladium(0), and a base such as potassiumcarbonate to give compounds of formula 6, wherein L is a direct bond.Alternatively, in the case where Z¹ is —CH₂—OH and B is aryl,heteroaryl, heterocyclyl, or cycloalkyl, compounds of formula 5 can betreated with a base such as sodium hydride and compounds of formula 4under heated conditions to give compounds of formula 6, wherein L is—CH₂—O—. In turn, compounds of formula 6 can be treated with aceticanhydride under heated conditions followed by methanol and water ormethanol and sodium hydroxide under ambient to heated conditions toprovide compounds of formula 7, wherein L is —CH₂—O— or a direct bond.

Alternatively, compounds of formula 7 (wherein B is aryl, heteroaryl,heterocyclyl, or cycloalkyl; R¹⁰, R¹¹, and R¹² are each independentlyselected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; and X isCH) can be prepared by treating compounds of formula 8 (wherein X¹ ischlorine, bromine or iodine; X² is —O—CH₃ or chlorine; and X is CH) withcompounds of formula 5 (wherein Z¹ is —B(OH)₂, —B(OR¹³)₂, —SnR¹³ ₃ orthe like and R¹³ is alkyl), a catalyst such as palladium(0), and a basesuch as potassium carbonate to give compounds of formula 9, wherein L isa direct bond. Alternatively, in the case where Z¹ is —CH₂—OH, compoundsof formula 5 can be treated with compounds of formula 8, a catalyst suchas copper iodide, a ligand such as 3,4,7,8-tetramethylphenanthroline anda base such as cesium carbonate under heated conditions to givecompounds of formula 9, wherein L is —CH₂—O—. In turn, compounds offormula 9 can be heated under acidic conditions to provide compounds offormula 7, wherein L is —CH₂—O— or a direct bond.

Alternatively, compounds of formula 7 (wherein B is aryl, heteroaryl,heterocyclyl, or cycloalkyl; R¹⁰, R¹¹, and R¹² are each independentlyselected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; and X isN) can be prepared from compounds of formula 10 (wherein X is N and R¹⁴is a protecting group such as tetrahydropyran-2-yl). The hydroxyl groupon compound 10 can be converted to an appropriate activating group togive compounds of formula 11. In the case where Z² is triflate,compounds of formula 10 can be treated with trifluoromethylsulfonicanhydride or N-phenyl trifluoromethanesulfonamide and a base such astriethylamine, pyridine or lithium bis(trimethylsilyl)amide under cooledconditions to give compounds of formula 11. Treatment of compounds offormula 11 with compounds of formula 5 (wherein B is aryl, heteroaryl,heterocyclyl, or cycloalkyl; R¹⁰, R¹¹, and R¹² are each independentlyselected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; Z¹ is—B(OH)₂, —B(OR¹³)₂, —SnR¹³ ₃ or the like, and R¹³ is alkyl), a catalystsuch as palladium(0), and a base such as potassium carbonate underheated conditions can provide compounds of formula 12, wherein L is adirect bond. Alternatively, in the case where Z¹ is —CH₂—Br, compoundsof formula 5 can be treated with compounds of formula 10 and a base suchas potassium carbonate to give compounds of formula 12, wherein L is—CH₂—O—. Removal of the protecting group R¹⁴ on compound 12 can providecompounds of formula 7, wherein L is —CH₂—O— or a direct bond.

Compounds of formula 13 (wherein B is aryl, heteroaryl, heterocyclyl, orcycloalkyl; L is —CH₂—O—, or a bond; X is CH or N; Z is CH or N; R¹ isH, alkyl or a protecting group such as tert-butoxycarbonyl,benzyloxycarbonyl or p-toluenesulfonyl; R¹⁰, R¹¹ and R¹² are eachindependently selected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃, and—CN; and n is 1 or 2) can be prepared by treating compounds of formula 3(wherein R¹ is H, alkyl or a protecting group such astert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl; Z is CH orN; and n is 1 or 2) under heated conditions with a catalyst such ascopper iodide, a ligand such as trans-1,2-diaminocyclohexane or8-hydroxyquinoline, a base such as potassium carbonate, cesium carbonateor potassium phosphate and compounds of formula 7 (wherein B is aryl,heteroaryl, heterocyclyl, or cycloalkyl; R¹⁰, R¹¹, and R¹² are eachindependently selected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃, and—CN; L is —CH₂—O— or a bond; and X is CH or N). In the case where R¹ isa protecting group, the protecting group can be removed to givecompounds of formula 13 wherein R¹ is H.

Compounds of formula 14 (wherein X is CH or N; Z is CH or N; R¹ is H,alkyl or a protecting group such as tert-butoxycarbonyl,benzyloxycarbonyl or p-toluenesulfonyl; and n is 1 or 2) can be treatedwith hydrogen and a catalyst such as palladium on carbon to providecompounds of formula 15. The hydroxyl group on compounds of formula 15can be converted to an appropriate activating group to give compounds offormula 16. In the case where Z² is triflate, compounds of formula 15can be treated with trifluoromethylsulfonic anhydride or N-phenyltrifluoromethanesulfonamide and a base such as pyridine or lithiumbis(trimethylsilyl)amide under cooled conditions to give compounds offormula 16. Treatment of compounds of formula 16 with compounds offormula 5 (wherein B is aryl, heteroaryl, heterocyclyl, or cycloalkyl;R¹⁰, R¹¹, and R¹² are each independently selected from H, alkoxy,—S-alkyl, alkyl, halo, —CF₃, and —CN; Z¹ is —B(OH)₂, —B(OR¹³)₂, —SnR¹³ ₃or the like and R¹³ is alkyl), a catalyst such as palladium(0), and abase such as potassium carbonate under heated conditions can providecompounds of formula 13, wherein L is a direct bond.

Compounds of formula 18 (wherein B is aryl, heteroaryl, heterocyclyl, orcycloalkyl; R¹⁰, R¹¹, and R¹² are each independently selected from H,alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; and L is —CH₂—CH₂—) can beprepared by treating piperazin-2-one 17 with compounds of formula 5(wherein Z¹ is —CH₂—CH₂—X¹; and X¹ is a leaving group such as chlorine,bromine, iodine or the like) and a base such as di-isopropylamine togive compounds of formula 18, wherein L is —CH₂—CH₂—.

Compounds of formula 19 (wherein B is aryl, heteroaryl, heterocyclyl, orcycloalkyl; R¹⁰, R¹¹, and R¹² are each independently selected from H,alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; L is —CH₂—CH₂—; Z is CH orN; R¹ is H, alkyl, or a protecting group such as tert-butoxycarbonyl,benzyloxycarbonyl or p-toluenesulfonyl; and n is 1 or 2) can be preparedby treating compounds of formula 3 (wherein Z is CH or N; R¹ is H,alkyl, or a protecting group such as tert-butoxycarbonyl,benzyloxycarbonyl or p-toluenesulfonyl; and n is 1 or 2) under heatedconditions with a catalyst such as copper iodide, a ligand such astrans-1,2-bis(methylamino)cyclohexane or 8-hydroxyquinoline, a base suchas potassium carbonate, cesium carbonate or potassium phosphate andcompounds of formula 18 (wherein B is aryl, heteroaryl, heterocyclyl, orcycloalkyl; R¹⁰, R¹¹, and R¹² are each independently selected from H,alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; and L is —CH₂—CH₂—). Inthe case where R¹ is a protecting group, the protecting group can beremoved to give compounds of formula 19 wherein R¹ is H.

The present invention provides compositions containing the compoundsdescribed herein, including, in particular, pharmaceutical compositionscomprising therapeutically effective amounts of the compounds andpharmaceutically acceptable carriers.

It is a further object of the present invention to provide kits having aplurality of active ingredients (with or without carrier) which,together, may be effectively utilized for carrying out the novelcombination therapies of the invention.

It is another object of the invention to provide a novel pharmaceuticalcomposition which is effective, in and of itself, for utilization in abeneficial combination therapy because it includes a plurality of activeingredients which may be utilized in accordance with the invention.

The present invention also provides kits or single packages combiningone or more active ingredients useful in treating the disease. A kit mayprovide (alone or in combination with a pharmaceutically acceptablediluent or carrier) the compounds of formula I and an additional activeingredient (alone or in combination with diluent or carrier), asdescribed above.

The products according to the present invention may be presented informs permitting administration by the most suitable route and theinvention also relates to pharmaceutical compositions containing atleast one product according to the invention which are suitable for usein human or veterinary medicine. These compositions may be preparedaccording to the customary methods, using one or more pharmaceuticallyacceptable adjuvants or excipients. The adjuvants comprise, inter alia,diluents, sterile aqueous media, and the various non-toxic organicsolvents. The compositions may be presented in the form of tablets,pills, granules, powders, aqueous solutions or suspensions, injectablesolutions, elixirs or syrups, and can contain one or more agents chosenfrom the group comprising sweeteners, flavorings, colorings, orstabilizers in order to obtain pharmaceutically acceptable preparations.

The formulations of compounds of formula I include those suitable fororal, parenteral (including subcutaneous, intradermal, intramuscular,intraperitoneal, intravenous, and intraarticular), rectal, colonic, andtopical (including dermal, buccal, nasal, sublingual, and intraocular)administration. The most suitable route may depend upon the conditionand disorder of the recipient. The formulations may conveniently bepresented in unit dosage form and may be prepared by any of the methodswell known in the art of pharmacy. Such methods include the step ofbringing into association a compound of formula I or a pharmaceuticallyacceptable salt or solvate thereof (“active ingredient”) with thecarrier, which constitutes one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both and then, if necessary, shapingthe product into the desired formulation.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets, or tablets each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution or a suspension in an aqueous liquid or a non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion. The active ingredient may also be presented as a bolus,electuary, or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active, ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide sustained, delayed, or controlled releaseof the active ingredient therein.

The pharmaceutical compositions may include a “pharmaceuticallyacceptable inert carrier” and this expression is intended to include oneor more inert excipients, which include starches, polyols, granulatingagents, microcrystalline cellulose, diluents, lubricants, binders,disintegrating agents, and the like. If desired, tablet dosages of thedisclosed compositions may be coated by standard aqueous or nonaqueoustechniques. “Pharmaceutically acceptable carrier” also encompassescontrolled release means.

Pharmaceutical compositions may also optionally include othertherapeutic ingredients, anti-caking agents, preservatives, sweeteningagents, colorants, flavors, desiccants, plasticizers, dyes, and thelike. Any such optional ingredient must be compatible with the compoundof formula Ito insure the stability of the formulation. The compositionmay contain other additives as needed, including for example lactose,glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose,maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol,mannitol, myoinositol, and the like, and hydrates thereof, and aminoacids, for example alanine, glycine and betaine, and peptides andproteins, for example albumen.

Examples of excipients for use as the pharmaceutically acceptablecarriers and the pharmaceutically acceptable inert carriers and theaforementioned additional ingredients include, but are not limited tobinders, fillers, disintegrants, lubricants, anti-microbial agents, andcoating agents.

The dose range for adult humans is generally from 0.001 mg to 10 g/dayorally. Tablets or other forms of presentation provided in discreteunits may conveniently contain an amount of compound of formula I whichis effective at such dosage or as a multiple of the same, for instance,units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. Theprecise amount of compound administered to a patient will be theresponsibility of the attendant physician. It will be understood,however, that the specific dose level for any particular patient willdepend upon a variety of factors including the activity of the specificcompound employed, the age, body weight, general health, sex, diet timeof administration, route of administration, rate of excretion, drugcombination, and the severity of the particular disease undergoingtherapy.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may vary fromabout 5 to about 95% of the total composition.

A dosage unit (e.g. an oral dosage unit) can include from, for example,0.01 to 0.1 mg, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g. 0.01 mg,1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg,400 mg, 450 mg, 500 mg) of a compound described herein.

The products according to the present invention may be administered asfrequently as necessary in order to obtain the desired therapeuticeffect. Some patients may respond rapidly to a higher or lower dose andmay find much weaker maintenance doses adequate. For other patients, itmay be necessary to have long-term treatments at the rate of 1 to 4doses per day, in accordance with the physiological requirements of eachparticular patient. Generally, the active product may be administeredorally 1 to 4 times per day. It goes without saying that, for otherpatients, it will be necessary to prescribe not more than one or twodoses per day.

For additional information about pharmaceutical compositions and theirformulation, see, for example, Remington, The Science and Practice ofPharmacy, 20^(th) Edition (2000), which is hereby incorporated byreference in its entirety.

The compounds of formula 1 can be administered, e.g., by intravenousinjection, intramuscular injection, subcutaneous injection,intraperitoneal injection, topical, sublingual, intraarticular (in thejoints), intradermal, buccal, ophthalmic (including intraocular),intranasally (including using a cannula), or by other routes. Thecompounds of formula I can be administered orally, e.g., as a tablet orcachet containing a predetermined amount of the active ingredient, gel,pellet, paste, syrup, bolus, electuary, slurry, capsule, powder,granules, as a solution or a suspension in an aqueous liquid or anon-aqueous liquid, as an oil-in-water liquid emulsion or a water-in-oilliquid emulsion, via a micellar formulation (see, e.g. PCT PublicationNo. WO 97/11682, which is hereby incorporated by reference in itsentirety) via a liposomal formulation (see, e.g., European Patent EP736299 and PCT Publication Nos. WO 99/59550 and WO 97/13500, which arehereby incorporated by reference in their entirety), via formulationsdescribed in PCT Publication No. WO 03/094886, which is herebyincorporated by reference in its entirety, or in some other form. Thecompounds of formula I can also be administered transdermally (i.e. viareservoir-type or matrix-type patches, microneedles, thermal poration,hypodermic needles, iontophoresis, electroporation, ultrasound or otherforms of sonophoresis, jet injection, or a combination of any of thepreceding methods (Prausnitz et al., Nature Reviews Drug Discovery 3:115(2004), which is hereby incorporated by reference in its entirety)). Thecompounds can be administered locally. The compounds can be coated on astent. The compounds can be administered using high-velocity transdermalparticle injection techniques using the hydrogel particle formulationdescribed in U.S. Patent Publication No. 20020061336, which is herebyincorporated by reference in its entirety. Additional particleformulations are described in PCT Publication Nos. WO 00/45792, WO00/53160, and WO 02/19989, which are hereby incorporated by reference intheir entirety. An example of a transdermal formulation containingplaster and the absorption promoter dimethylisosorbide can be found inPCT Publication No. WO 89/04179, which is hereby incorporated byreference in its entirety. PCT Publication No. WO 96/11705, which ishereby incorporated by reference in its entirety, provides formulationssuitable for transdermal administration.

The compounds can be administered in the form a suppository or by othervaginal or rectal means. The compounds can be administered in atransmembrane formulation as described in PCT Publication No. WO90/07923, which is hereby incorporated by reference in its entirety. Thecompounds can be administered non-invasively via the dehydratedparticles described in U.S. Pat. No. 6,485,706, which is herebyincorporated by reference in its entirety. The agent can be administeredin an enteric-coated drug formulation as described in PCT PublicationNo. WO 02/49621, which is hereby incorporated by reference in itsentirety. The compounds can be administered intranasaly using theformulation described in U.S. Pat. No. 5,179,079, which is herebyincorporated by reference in its entirety. Formulations suitable forparenteral injection are described in PCT Publication No. WO 00/62759,which is hereby incorporated by reference in its entirety. The compoundscan be administered using the casein formulation described in U.S.Patent Application Publication No. 20030206939 and PCT Publication No.WO 00/06108, which are hereby incorporated by reference in theirentirety. The compounds can be administered using the particulateformulations described in U.S. Patent Application Publication No.20020034536, which is hereby incorporated by reference in its entirety.

The compounds, alone or in combination with other suitable components,can be administered by pulmonary route utilizing several techniquesincluding but not limited to intratracheal instillation (delivery ofsolution into the lungs by syringe), intratracheal delivery ofliposomes, insufflation (administration of powder formulation by syringeor any other similar device into the lungs), and aerosol inhalation.Aerosols (e.g., jet or ultrasonic nebulizers, metered-dose inhalers(MDIs), and dry-Powder inhalers (DPIs)) can also be used in intranasalapplications. Aerosol formulations are stable dispersions or suspensionsof solid material and liquid droplets in a gaseous medium and can beplaced into pressurized acceptable propellants, such ashydrofluoroalkanes (HFAs, i.e. HFA-134a and HFA-227, or a mixturethereof), dichlorodifluoromethane (or other chlorofluorocarbonpropellants such as a mixture of Propellants 11, 12, and/or 114),propane, nitrogen, and the like. Pulmonary formulations may includepermeation enhancers such as fatty acids, and saccharides, chelatingagents, enzyme inhibitors (e.g., protease inhibitors), adjuvants (e.g.,glycocholate, surfactin, span 85, and nafamostat), preservatives (e.g.,benzalkonium chloride or chlorobutanol), and ethanol (normally up to 5%but possibly up to 20%, by weight). Ethanol is commonly included inaerosol compositions as it can improve the function of the meteringvalve and in some cases also improve the stability of the dispersion.

Pulmonary formulations may also include surfactants which include butare not limited to bile salts and those described in U.S. Pat. No.6,524,557 and references therein, which is hereby incorporated byreference in its entirety. The surfactants described in U.S. Pat. No.6,524,557, which is hereby incorporated by reference in its entirety,e.g., a C₈-C₁₆ fatty acid salt, a bile salt, a phospholipid, or alkylsaccharide are advantageous in that some of them also reportedly enhanceabsorption of the compound in the formulation.

Also suitable in the invention are dry powder formulations comprising atherapeutically effective amount of active compound blended with anappropriate carrier and adapted for use in connection with a dry-powderinhaler. Absorption enhancers that can be added to dry powderformulations of the present invention include those described in U.S.Pat. No. 6,632,456, which is hereby incorporated by reference in itsentirety. PCT Publication No. WO 02/080884, which is hereby incorporatedby reference in its entirety, describes new methods for the surfacemodification of powders. Aerosol formulations may include U.S. Pat. No.5,230,884, U.S. Pat. No. 5,292,499, PCT Publication No. WO 017/8694, PCTPublication No. WO 01/78696, U.S. Patent Application Publication No.2003019437, U.S. Patent Application Publication No. 20030165436, and PCTPublication No. WO 96/40089 (which includes vegetable oil), which arehereby incorporated by reference in their entirety. Sustained releaseformulations suitable for inhalation are described in U.S. PatentApplication Publication Nos. 20010036481A1, 20030232019A1, and20040018243A1 as well as in PCT Publication Nos. WO 01/13891, WO02/067902, WO 03/072080, and WO 03/079885, which are hereby incorporatedby reference in their entirety.

Pulmonary formulations containing microparticles are described in PCTPublication No. WO 03/015750, U.S. Patent Application Publication No.20030008013, and PCT Publication No. WO 00/00176, which are herebyincorporated by reference in their entirety. Pulmonary formulationscontaining stable glassy state powder are described in U.S. PatentApplication Publication No. 20020141945 and U.S. Pat. No. 6,309,671,which are hereby incorporated by reference in their entirety. Otheraerosol formulations are described in EP 1338272A1, PCT Publication No.WO 90/09781, U.S. Pat. No. 5,348,730, U.S. Pat. No. 6,436,367, PCTPublication No. WO 91/04011, and U.S. Pat. No. 6,294,153, which arehereby incorporated by reference in their entirety, and U.S. Pat. No.6,290,987, which is hereby incorporated by reference in its entirety,describes a liposomal based formulation that can be administered viaaerosol or other means.

Powder formulations for inhalation are described in U.S. PatentApplication Publication No. 20030053960 and PCT Publication No. WO01/60341, which are hereby incorporated by reference in their entirety.The compounds can be administered intranasally as described in U.S.Patent Application Publication No. 20010038824, which is herebyincorporated by reference in its entirety.

Solutions of medicament in buffered saline and similar vehicles arecommonly employed to generate an aerosol in a nebulizer. Simplenebulizers operate on Bernoulli's principle and employ a stream of airor oxygen to generate the spray particles. More complex nebulizersemploy ultrasound to create the spray particles. Both types are wellknown in the art and are described in standard textbooks of pharmacysuch as Sprowls' American Pharmacy and Remington's The Science andPractice of Pharmacy, which are hereby incorporated by reference intheir entirety.

Other devices for generating aerosols employ compressed gases, usuallyhydrofluorocarbons and chlorofluorocarbons, which are mixed with themedicament and any necessary excipients in a pressurized container,these devices are likewise described in standard textbooks such asSprowls and Remington, which are hereby incorporated by reference intheir entirety.

Compounds of formula I can be incorporated into a liposome to improvehalf-life. Compounds of formula I can also be conjugated to polyethyleneglycol (PEG) chains. Methods for pegylation and additional formulationscontaining PEG-conjugates (i.e. PEG-based hydrogels, PEG modifiedliposomes) can be found in Harris et al., Nature Reviews Drug Discovery,2:214-221 (2003) and the references therein, which are herebyincorporated by reference in their entirety. Compounds of formula I canalso be administered via a nanocochleate or cochleate delivery vehicle(BioDelivery Sciences International, Raleigh, N.C.). Compounds offormula I can also be delivered using nanoemulsion formulations.

EXAMPLES

The examples set forth below are for illustrative pirposes only and arenot intended to limit, in any way, the scope of the present invention.

Example 1 Analytical Methods and Materials

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectrawere obtained on Bruker spectrometers at 300, 400 or 500 MHz. Spectraare given in ppm (δ) and coupling constants, J, are reported in Hertz.Tetramethylsilane (TMS) was used as an internal standard. Mass spectrawere collected using either a Finnigan LCQ Duo LCMS ion trapelectrospray ionization (ESI) or a mass Varian 1200 L single quadrapolemass spectrometer (ESI). High performace liquid chromatograph (HPLC)analyses were obtained using a Luna C18(2) column (250×4.6 mm,Phenomenex) or a Gemini C18 column (250×4.6 mm, Phenomenex) with UVdetection at 254 nm or 223 nm using a standard solvent gradient program(Method A, Method B or Method C).

Method A: Time Flow (min) (mL/min) % A % B 0.0 1.0 98.0 2.0 10 1.0 5.095.0 15 1.0 5.0 95.0 A = Water with 0.05% Trifluoroacetic Acid B =Acetonitrile with 0.05% Trifluoroacetic Acid

Method B: Time Flow (min) (mL/min) % A % B 0.0 15 90.0 10.0 10 15 75.025.0 25 15 70.0 30.0 30 15 5.0 95.0 33 15 5.0 95.0 A = Water with 0.025%Trifluoroacetic Acid B = Acentonitrile with 0.025% Trifluoroacetic Acid

Method C: Time Flow (min) (mL/min) % A % B 0.0 1.0 90.0 10.0 20 1.0 10.090.0 30 1.0 10.0 90.0 A = Water with 0.025% Trifluoroacetic Acid B =Acetonitrile with 0.025% Trifluoroacetic Acid

Example 2 Preparation of4-(Benzyloxy)-1-(6-methyl-3,4,5,6-tetrahydro-1H-2,5-methanoazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) 1-(3-Bromophenyl)-1-methylhydrazine (CAS Registry Number 90084-67-6)(Stroh et al., Chemische Berichte 97:83-87 (1964), which is herebyincorporated by reference in its entirety)

To a solution of 3-bromophenylhydrazine hydrochloride (15 g, 67 mmol) inanhydrous THF (360 mL) was added LiHMDS (1.0 M solution in THF, 127 mL,127 mmol) dropwise over a period of 1 h at 0° C. The reaction mixturewas stirred for 30 min while warming to room temperature. The flask wasrecooled to −78° C., and MeI (4.1 mL, 67 mmol) was added. The reactionmixture was stirred for 2 h at 0° C. and then was quenched with water(600 mL). The aqueous layer was extracted with methylene chloride (3×200mL), and the combined organic layers were dried over sodium sulfate,filtered, and concentrated under reduced pressure. Purification by flashcolumn chromatography (silica gel, hexanes/EtOAc, 60:40) gave the titlecompound (10.2 g, 76%) as yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.18 (t,J=3.5 Hz, 1H), 7.08 (t, J=13.5 Hz, 1H), 6.91-6.86 (m, 2H), 3.69 (br s,2H), 3.11 (s, 3H).

b) 1-Azabicyclo[3.2.1]octan-4-one (CAS Registry Number 17604-77-2)(Thill et al., Journal of Organic Chemistry 33:4376-4380 (1968), whichis hereby incorporated by reference in its entirety)

This compound was prepared in accordance with the procedure of King etal., J. Med. Chem., 36:683-689 (1993), which is hereby incorporated byreference in its entirety.

c)8-Bromo-6-methyl-3,4,5,6-tetrahydro-1H-2,5-methanoazepino[4,3-b]indole

1-(3-Bromophenyl)-1-methylhydrazine (0.48 g, 2.3 mmol) and1-azabicyclo[3.2.1]octan-4-one (0.33 g, 2.6 mmol) were dissolved inisopropanol (3 mL), and concentrated aqueous HCl (0.75 mL) was added.The reaction mixture was heated to reflux for 18 h, concentrated andbasified using 2 N NaOH. The aqueous layer was extracted with methylenechloride (3×). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated to dryness. The residue was purified by flashcolumn chromatography (silica gel, 10%-100% solvent mixture B in ethylacetate; solvent mixture B=80:18:2 ethyl acetate/methanol/concentratedammonium hydroxide) to give the title compound (634 mg, 95%) as a yellowsemisolid: ¹H NMR (300 MHz, CDCl₃) δ 7.42 (d, J=2.5 Hz, 1H), 7.20 (d,J=13.5 Hz, 1H), 7.14 (d, J=13.5 Hz, 1H), 4.40 (d, J=26.5 Hz, 1H), 3.72(d, J=26.0 Hz, 1H), 3.63 (s, 3H), 3.34-3.25 (m, 1H), 3.20-3.17 (m, 2H),3.17-3.13 (m, 1H), 2.97-2.92 (m, 1H), 2.87-2.76 (m, 2H).

d)4-(Benzyloxy)-1-(6-methyl-3,4,5,6-tetrahydro-1H-2,5-methanoazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

8-Bromo-6-methyl-3,4,5,6-tetrahydro-1H-2,5-methanoazepino[4,3-b]indole(0.30 g, 1.0 mmol), 4-benzyloxypyridone (0.22 g, 1.1 mmol), K₂CO₃ (0.28g, 2.0 mmol), 8-hydroxyquinoline (0.22 g, 1.5 mmol), and copper iodide(0.29 g, 1.5 mmol) were suspended in DMSO (20 mL) and purged with argonfor ˜5 min. The reaction mixture was heated at 135° C. for 18 h. Aftercooling to room temperature, the mixture was diluted with methylenechloride and filtered through Celite. The filtrate was washed with H₂O(3×), dried over Na₂SO₄, filtered and concentrated to dryness.Purification by flash column chromatography (silica gel, 0%-100% solventmixture B in methylene chloride; solvent mixture B=80:18:2 methylenechloride/methanol/concentrated ammonium hydroxide) gave the free base ofthe title compound (13 mg) as a white solid. The free base was convertedto the HCl salt with 2 equivalents of 2 M HCl in Et₂O to provide thetitle compound (14 mg) as a yellow solid. Free Base: ¹H NMR (500 MHz,CDCl₃) δ 7.56 (d, J=7.6 Hz, 1H), 7.47-7.34 (m, 7H), 6.99 (dd, J=6.5, 1.8Hz, 1H), 6.28 (dd, J=4.9, 2.6 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 5.17 (s,2H), 4.62-4.55 (m, 1H), 4.12-4.09 (m, 1H), 3.75 (s, 3H), 3.63-3.56 (m,1H), 3.55-3.45 (m, 1H), 3.45-3.43 (m, 2H), 3.10-3.00 (m, 1H), 2.34-2.32(m, 1H), 2.22-1.99 (m, 1H). HCl salt: ¹H NMR (500 MHz, CD₃OD) δ 7.57 (d,J=7.5 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.48-7.06 (m, 6H), 7.06 (dd,J=6.5, 1.8 Hz, 1H), 6.31 (dd, J=4.8, 2.7 Hz, 1H), 6.13 (d, J=2.6 Hz,1H), 5.18 (s, 2H), 4.92-4.87 (m, 1H), 4.54 (d, J=14.0, 1H), 3.94-3.92(m, 2H), 3.81-3.77 (m, 4H), 3.71 (dd, J=7.0, 3.5 Hz, 1H), 3.44-3.42 (m,1H), 2.57-2.51 (m, 1H), 2.40-2.30 (m, 1H); ESI MS m/z 412 [M+H]⁺; HPLC(Method A) 98.1% (AUC), t_(R)=7.5 min.

Example 3 Preparation of4-(Benzyloxy)-1-(6-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) 1-Azabicyclo[3.2.2]nonan-4-one (CAS Registry Number 30708-54-4)(Vorob'eva et al., Khimiya Geterotsiklicheskikh Soedinenii 8:1037-1040(1970), which is hereby incorporated by reference in its entirety)

This compound was prepared in accordance with the procedure of Lai etal., J. Med. Chem., 40:226-235 (1997), which is hereby incorporated byreference in its entirety.

b) 8-Bromo-6-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

1-(3-Bromophenyl)-1-methylhydrazine (0.50 g, 2.5 mmol) and1-azabicyclo[3.2.2]nonan-4-one (0.38 g, 2.7 mmol) were dissolved inisopropanol (4 mL), and concentrated aqueous HCl (0.8 mL) was added. Thereaction mixture was heated to reflux for 18 h, concentrated andbasified using 2 N NaOH. The aqueous layer was extracted with methylenechloride (3×). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated to dryness. The residue was purified by flashcolumn chromatography (silica gel, 0%-100% solvent mixture B inmethylene chloride; solvent mixture B=80:18:2 methylenechloride/methanol/concentrated ammonium hydroxide) to give the titlecompound (438 mg, 58%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.40(d, J=2.0 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 4.25(s, 2H), 3.61 (s, 3H), 3.30-3.24 (m, 3H), 3.14-3.08 (m, 2H), 2.02-1.99(m, 4H).

c)4-(Benzyloxy)-1-(6-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

8-Bromo-6-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(268 mg, 0.879 mmol), 4-benzyloxypyridone (194 mg, 0.967 mmol), K₂CO₃(240 mg, 1.74 mmol), 8-hydroxyquinoline (189 mg, 1.32 mmol), and copperiodide (248 mg, 1.30 mmol) were suspended in DMSO (25 mL) and purgedwith argon for ˜5 min. The reaction mixture was heated to 135° C. for 48h. After cooling to room temperature, the mixture was diluted withmethylene chloride and filtered through Celite. The filtrate was washedwith H₂O (3×), dried over Na₂SO₄, filtered and concentrated to dryness.Purification by flash column chromatography (silica gel, 0%-100% solventmixture B in methylene chloride; solvent mixture B=80:18:2 methylenechloride/methanol/concentrated ammonium hydroxide) gave the free base ofthe title compound (62 mg) as a yellow solid. A portion of the free basewas converted to the HCl salt according to the procedure of Example 2(step d) to give the title compound (68 mg) as a yellow solid. FreeBase: ¹H NMR (500 MHz, CDCl₃) δ 7.52 (d, J=7.6 Hz, 1H), 7.45-7.32 (m,7H), 6.93 (d, J=8.2 Hz, 1H), 6.24 (dd, J=5.1, 2.3 Hz, 1H), 6.10 (d,J=2.3 Hz, 1H), 5.14 (s, 2H), 4.26 (br s, 2H), 3.66 (s, 3H), 3.31-3.23(m, 3H), 3.04-3.00 (m, 2H), 2.14-2.09 (m, 2H), 2.05-2.01 (m, 2H). HClsalt: ¹H NMR (500 MHz, CD₃OD) δ 7.69 (d, J=7.5 Hz, 1H), 7.54 (d, J=8.4Hz, 1H), 7.49-7.36 (m, 5H), 7.08 (dd, J=6.6, 1.7 Hz, 1H), 6.45 (dd,J=4.9, 2.7 Hz, 1H), 6.24 (d, J=2.7 Hz, 1H), 5.23 (s, 2H), 4.79 (s, 2H),3.77-3.92 (s, 3H), 3.70-3.60 (m, 4H), 3.52-3.47 (m, 2H), 2.46-2.40 (m,2H), 2.27-2.26 (m, 2H); ESI MS m/z 426 [M+H]⁺; HPLC (Method A) 98.0%(AUC), t_(R)=7.6 min.

Example 4 Preparation of4-((5-Fluoropyridin-2-yl)methoxy)-1-(6-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) 4((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide (CAS Registry Number1173155-63-9) (WO 2009/089482 to Guzzo et al., which is herebyincorporated by reference in its entirety)

5-Fluoro-2-pyridylbenzylalcohol (3.00 g, 23.6 mmol) was dissolved in DMF(20 mL), and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol)was added. After stirring for 30 minutes, 4-chloropyridine-N-oxide (2.03g, 15.7 mmol) was added, and the reaction mixture was heated for 1 h at120° C. Upon cooling, the mixture was diluted with methylene chlorideand washed with 5% lithium chloride solution (5×), dried andconcentrated. Purification by flash column chromatography (40 g ISCOcolumn eluting with methylene chloride and a methanol/ammonia mixture(10:1); gradient 100% methylene chloride to 90% methylene chloride over30 min at 40 mL/min) provided the title compound (1.76 g, 50%) as a tansolid: ¹H NMR (300 MHz, CDCl₃) δ 8.48 (s, 1H), 8.12 (d, J=7.7 Hz, 2H),7.48-7.46 (m, 2H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s, 2H).

b) 4((5-Fluoroyridin-2-Amethoxy)pyridin-2(1H)-one (CAS Registry Number924311-90-0) (WO 2007/018248 to Ando et al., which is herebyincorporated by reference in its entirety)

4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide (1.76 g, 7.99 mmol)was heated to 140° C. in acetic anhydride (80 mL) for 5 h. The mixturewas concentrated and then heated at 80° C. for 1 h in a mixture of MeOH(20 mL) and aqueous 1 N NaOH (15 mL). The resulting black solution wasconcentrated to a volume of 15 mL, and the solid was filtered off,rinsed with CH₂Cl₂ and dried under vacuum to provide the title compound(1.29 g, 73%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.12 (s,1H), 8.59 (d, J=2.9 Hz, 1H), 7.79 (dt, J=8.7, 2.9 Hz, 1H), 7.60 (dd,J=8.7, 4.5 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H), 5.95 (dd, J=7.4, 2.6 Hz,1H), 5.78 (d, J=2.5 Hz, 1H), 5.12 (s, 2H).

c)4-(5-Fluoropyridin-2-yl)methoxy)-1-(6-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

8-Bromo-6-methyl-3,4,5,6-tetrahydro-1H-2,5-ethano azepino[4,3-b]indole(323 mg, 1.06 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one(243 mg, 1.16 mmol), K₂CO₃ (276 mg, 1.99 mmol), 8-hydroxyquinoline (217mg, 1.49 mmol), and copper iodide (285 mg, 1.50 mmol) were suspended inDMSO (30 mL) and purged with argon for ˜5 min. The reaction mixture washeated to 135° C. for 48 h. After cooling to room temperature, themixture was diluted with methylene chloride and filtered through Celite.The filtrate was washed with H₂O (3×), dried over Na₂SO₄, filtered andconcentrated to dryness. Purification by flash column chromatography(silica gel, 0%-100% solvent mixture B in methylene chloride; solventmixture B=80:18:2 methylene chloride/methanol/concentrated ammoniumhydroxide) gave the free base of the title compound (86 mg) as a yellowoil. A portion of the free base was converted to the HCl salt accordingto the procedure of Example 2 (step d) to give the title compound (30mg) as an off-white solid. Free Base: ¹H NMR (500 MHz, CDCl₃) δ 8.49 (d,J=2.5 Hz, 1H), 7.51-7.46 (m, 2H), 7.44 (d, J=8.5 Hz, 1H), 7.33 (d, J=7.5Hz, 1H), 7.27 (d, J=1.5 Hz, 1H), 6.98 (dd, J=6.5, 2.0 Hz, 1H), 6.08 (d,J=2.5 Hz, 1H), 6.07 (s, 1H), 5.17 (s, 2H), 4.31-4.30 (br s, 2H), 3.65(s, 3H), 3.30-3.29 (m, 2H), 3.18-3.16 (m, 1H), 3.11-3.05 (m, 2H),2.08-1.99 (m, 4H). HCl salt: ¹H NMR (500 MHz, CD₃OD) δ 8.57 (d, J=2.5Hz, 1H), 7.81-7.77 (m, 1H), 7.74-7.71 (m, 1H), 7.69 (d, J=7.5 Hz, 1H),7.54 (d, J=8.5 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.07 (dd, J=6.5, 2.0 Hz,1H), 6.45 (dd, J=5.0, 2.5 Hz, 1H), 6.23 (d, J=2.5 Hz, 1H), 5.33 (s, 2H),4.79 (br s, 2H), 3.77 (s, 3H), 3.70-3.60 (m, 3H), 3.52-3.47 (m, 2H),2.46-2.43 (m, 2H), 2.30-2.20 (m, 2H); ESI MS m/z 445 [M+H]⁺; HPLC(Method A) 96.4% (AUC), t_(R)=6.7 min.

Example 5 Preparation of1-(6-Methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onehydrochloride

a) 3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine (CAS RegistryNumber 1173155-65-4) (WO 2009/089482 to Guzzo et al., which is herebyincorporated by reference in its entirety)

3-Chloro-6-(trifluoromethyl)pyridazine (137 mg, 0.751 mmol),2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (176mg, 0.749 mmol), K₂CO₃ (310 mg, 2.25 mmol) and PdCl₂(dppf) (61 mg, 0.075mmol) were stirred in DMSO (4 mL). The reaction mixture was degassed,then back-filled with N₂. The reaction mixture was stirred at 80° C. ina pre-heated oil bath for 2 hours. After cooling, the reaction wasquenched with water and extracted with CH₂Cl₂. The organic layer waswashed with H₂O and 5% LiCl, dried with Na₂SO₄, filtered andconcentrated. Flash chromatography (silica gel, hexanes/EtOAc), 100:0 to50:50) afforded the title compound (115 mg, 60%) as a white solid: ¹HNMR (500 MHz, CDCl₃) δ 8.39 (d, J=5.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H),7.94 (d, J=8.8 Hz, 1H), 7.62 (dd, J=5.4, 1.5 Hz, 1H), 7.45 (s, 1H), 4.03(s, 3H).

b) 4-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (CAS RegistryNumber 1173155-66-2) (WO 2009/089482 to Guzzo et al., which is herebyincorporated by reference in its entirety)

3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine (115 mg, 0.451mmol) was stirred in concentrated hydrochloric acid (20 mL) at 120° C.for 18 h and then concentrated. The residue was adjusted to pH 8 with 6N NaOH and the solids were filtered off, washed with water and driedunder vacuum to provide the title compound (120 mg, quant) as a whitesolid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.87 (s, 1H), 8.61 (d, J=8.9 Hz,1H), 8.42 (d, J=8.9 Hz, 1H), 7.62 (d, J=6.8 Hz, 1H), 7.19 (s, 1H), 7.01(dd, J=6.8, 1.6 Hz, 1H).

c)1-(6-Methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onehydrochloride

8-Bromo-6-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(322 mg, 1.05 mmol),4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (280 mg, 1.16mmol), K₂CO₃ (290 mg, 2.10 mmol), 8-hydroxyquinoline (228 mg, 1.57mmol), and copper iodide (300 mg, 1.58 mmol) were suspended in DMSO (30mL) and purged with argon for ˜5 min. The reaction mixture was heated to135° C. for 48 h. After cooling to room temperature, the mixture wasdiluted with methylene chloride and filtered through Celite. Thefiltrate was washed with H₂O (3×), dried over Na₂SO₄, filtered andconcentrated to dryness. Purification by flash column chromatography(silica gel, 0%-100% solvent mixture B in methylene chloride; solventmixture B=80:18:2 methylene chloride/methanol/concentrated ammoniumhydroxide) gave the free base of the title compound (93 mg) as a yellowsolid. A portion of the free base was converted to the HCl saltaccording to the procedure of Example 2 (step d) to give the titlecompound (46 mg) as a yellow solid. Free Base: ¹H NMR (500 MHz, CDCl₃) δ8.12 (d, J=15.0 Hz, 1H), 7.99 (d, J=15.0 Hz, 1H), 7.66 (d, J=13.0 Hz,1H), 7.51 (d, J=13.5 Hz, 1H), 7.37 (s, 1H), 7.28-7.20 (m, 2H), 7.09 (d,J=14.0 Hz, 1H), 4.37 (br s, 2H), 3.69 (s, 3H), 3.38-3.35 (m, 2H),3.24-3.18 (m, 1H), 3.15-3.08 (m, 2H), 2.11-2.06 (m, 4H). HCl salt: ¹HNMR (500 MHz, CD₃OD) δ 8.54 (d, J=9.0 Hz, 1H), 8.28 (d, J=8.5 Hz, 1H),7.91 (d, J=7.0 Hz, 1H), 7.60-7.57 (m, 2H), 7.44 (d, J=1.5 Hz, 1H), 7.34(dd, J=5.0, 2.0 Hz, 1H), 7.17 (dd, J=6.5, 2.0 Hz, 1H), 4.81 (br s, 2H),3.80 (s, 3H), 3.71-3.62 (m, 3H), 3.54-3.49 (m, 2H), 2.47-2.43 (m, 2H),2.35-2.25 (m, 2H); ESI MS m/z 466 [M+H]⁺;HPLC (Method A) 96.4% (AUC),t_(R)=7.1 min.

Example 6 Preparation of1-(6-Methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onehydrochloride

a) 2′-Methoxy-5-(trifluoromethyl)-2,4′-bipyridine (CAS Registry Number1108184-24-2) (WO 2009/015037 to Guzzo et al., which is herebyincorporated by reference in its entirety)

2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol),2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500mg, 1.81 mmol), K₂CO₃ (749 mg, 5.43 mmol) and PdCl₂(dppf) (140 mg, 0.18mmol) were stirred in DMSO (10 mL). The reaction mixture was degassed,then back-filled with N₂. The reaction mixture was stirred at 80° C. ina pre-heated oil bath for 2 hours. After cooling, the reaction wasquenched with water and extracted with CH₂Cl₂. The organic layer waswashed with H₂O and 5% LiCl, dried with Na₂SO₄, filtered andconcentrated. Flash chromatography (silica gel, hexanes/EtOAc, 100:0 to50:50) afforded the title compound title compound (337 mg, 62%) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 8.96 (s, 1H), 8.31 (d, J=5.4 Hz,1H), 8.04 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.51 (dd,J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).

b) 4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (CAS RegistryNumber 1108184-25-3) (WO 2009/015037 to Guzzo et al., which is herebyincorporated by reference in its entirety)

2′-Methoxy-5-(trifluoromethyl)-2,4′-bipyridine (337 mg, 1.32 mmol) wasstirred in concentrated hydrochloric acid (20 mL) at 120° C. for 18 hand then concentrated. The residue was adjusted to pH 8 with 6 N NaOH,and the solids were filtered off, washed with water and dried undervacuum to provide the title compound (289 mg, 89%) as a white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 11.08 (s, 1H) 9.10 (s, 1H), 8.35 (dd, J=8.4,2.1 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H), 7.53 (d, J=6.8, 1H), 7.09 (d, J=1.3Hz, 1H), 6.90 (dd, J=6.8, 1.6 Hz, 1H).

c)1-(6-Methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onehydrochloride

8-Bromo-6-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(336 mg, 1.10 mmol),4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (289 mg, 1.21mmol), K₂CO₃ (304 mg, 2.20 mmol), 8-hydroxyquinoline (239 mg, 1.64mmol), and copper iodide (314 mg, 1.65 mmol) were suspended in DMSO (30mL) and purged with argon for ˜5 min. The reaction mixture was heated to135° C. for 48 h. After cooling to room temperature, the mixture wasdiluted with methylene chloride and filtered through Celite. Thefiltrate was washed with H₂O (3×), dried over Na₂SO₄, filtered andconcentrated to dryness. Purification by flash column chromatography(silica gel, 0%-100% solvent mixture B in methylene chloride; solventmixture B=80:18:2 methylene chloride/methanol/concentrated ammoniumhydroxide) gave the free base of the title compound (80 mg) as a yellowsolid. A portion of the free base was converted to the HCl saltaccording to the procedure of Example 2 (step d) to give the titlecompound (35 mg) as a yellow solid. Free Base: ¹H NMR (500 MHz, CDCl₃) δ9.00 (s, 1H), 8.07 (dd, J=6.5, 2.0 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.58(d, J=7.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.26(s, 1H), 7.07-7.02 (m, 2H), 4.35 (br s, 2H), 3.68 (s, 3H), 3.40-3.34 (m,2H), 3.22-3.21 (m, 1H), 3.14-3.09 (m, 2H), 2.09-2.03 (m, 4H). HCl salt:¹H NMR (500 MHz, CD₃OD) δ 9.05 (d, J=2.0 Hz, 1H), 8.29 (dd, J=6.0, 2.0Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.58-7.56 (m,2H), 7.40 (d, J=1.5 Hz, 1H), 7.26 (dd, J=5.0, 2.0 Hz, 1H), 7.16 (dd,J=6.5, 2.0 Hz, 1H), 4.81 (br s, 2H), 3.80 (s, 3H), 3.71-3.62 (m, 3H),3.54-3.50 (m, 2H), 2.47-2.44 (m, 2H), 2.35-2.25 (m, 2H); ESI MS m/z 465[M+H]⁺; HPLC (Method A) 97.4% (AUC), t_(R)=7.6 min.

Example 7 Preparation of1-(6-Methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-8-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-onehydrochloride

a) 2-Methoxy-4((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridine (CASRegistry Number 1173155-95-7) (WO 2009/089482 to Guzzo et al., which ishereby incorporated by reference in its entirety)

4-Bromo-2-methoxypyridine (3.06 g, 16.2 mmol),(6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol),3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), CuI (0.14 g, 0.74mmol) and Cs₂CO₃ (7.57 g, 23.2 mmol) were combined in toluene (15 mL)and heated to reflux under a nitrogen atmosphere for 16 h. Upon coolingthe mixture was purified by flash column chromagraphy (silica gel,hexanes/EtOAc, 1:0 to 1:1) to provide the title compound (3.19 g, 72%)as a red oil: ¹H NMR (300 MHz, CDCl₃) δ 8.78 (s, 1H), 8.02 (d, J=5.9 Hz,1H), 7.95 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9,2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).

b) 4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (CASRegistry Number 1173155-96-8) (WO 2009/089482 to Guzzo et al., which ishereby incorporated by reference in its entirety)

2-Methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridine (3.19 g,11.2 mmol) was reacted according to the procedure of Example 5 (step b)to provide the title compound (2.04 g, 67%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 11.2 (br s, 1H), 8.84 (s, 1H), 8.14 (d, J=8.5 Hz,1H), 7.96 (d, J=8.0 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 5.95 (dd, J=7.3,2.5 Hz, 1H), 5.82 (d, J=2.4 Hz, 1H), 5.25 (s, 2H).

c)1-(6-Methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-8-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-onehydrochloride

8-Bromo-6-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(300 mg, 0.980 mmol),4-(6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (267 mg,0.980 mmol), K₂CO₃ (406 mg, 2.94 mmol), 8-hydroxyquinoline (71.0 mg,0.490 mmol), and copper iodide (280 mg, 1.47 mmol) were suspended inDMSO (10 mL) and purged with argon for ˜5 min. The reaction mixture washeated to 135° C. for 18 h. After cooling to room temperature, themixture was diluted with methylene chloride and filtered through Celite.The filtrate was washed with H₂O (3×), dried over Na₂SO₄, filtered andconcentrated to dryness. Purification by preparative thin layerchromatography (TLC) (silica gel, 80:18:2 methylenechloride/methanol/concentrated ammonium hydroxide) gave the free base ofthe title compound (72 mg) as an off-white solid. The free base wasconverted to the HCl salt with 2 equivalents of 2 M HCl in Et₂O toprovide the title compound (66.0 mg) as an off-white solid: ¹H NMR (500MHz, CD₃OD) δ 8.85 (s, 1H), 8.18-8.16 (dd, J=8.0, 1.5 Hz, 1H), 7.90 (d,J=8.0 Hz, 1H), 7.65 (d, J=7.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.48 (d,J=1.5 Hz, 1H), 7.08-7.05 (dd, J=8.0, 1.5 Hz, 1H), 6.40-6.37 (dd, J=7.5,3.0 Hz, 1H), 6.21 (d, J=2.5 Hz, 1H), 5.37 (s, 2H), 4.79 (br s, 2H), 3.77(s, 3H), 3.70-3.64 (m, 2H), 3.63-3.60 (m, 1H), 3.53-3.47 (m, 2H),2.46-2.42 (m, 2H), 2.29-2.23 (m, 2H); ESI MS m/z 495 [M+H]⁺; HPLC(Method A, 254 nm) 95.2% (AUC), t_(R)=12.9 min.

Example 8 Preparation of4-(Benzyloxy)-1-(10-methyl-7,8,9,10-tetrahydro-5H-6,9-ethanopyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

a) 2-Bromo-6-(1-methylhydrazinyl)pyridine

A suspension of 2,6-dibromopyridine (10.0 g, 42.0 mmol) in anhydrousmethylhydrazine (10 mL) was heated at 100° C. for 2 h. The mixture wascooled to room temperature and washed with water (3×20 mL). The organiclayer was separated, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. Purification by flash columnchromatography (silica gel, hexanes/EtOAc, 80:20) gave the titlecompound (5.70 g, 66%) as white solid: ¹H NMR (500 MHz, CDCl₃) δ7.30-7.26 (dd, J=8.5, 7.8Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.73 (d, J=7.0Hz, 1H), 4.03 (br s, 2H), 3.36 (s, 3H).

b)(Z)-4-(2-(6-Bromopyridin-2-yl)-2-methylhydrazono)-1-azabicyclo[3.2.2]nonane

A solution of 2-bromo-6-(1-methylhydrazinyl)pyridine (4.50 g, 22.2mmol), 1-azabicyclo[3.2.2]nonan-4-one (3.00 g, 22.2 mmol) andp-toluenesulphonic acid (844 mg, 4.40 mmol) in toluene (140 mL) washeated under reflux, with water removal (azeotrope), for 4 h. Themixture was concentrated and made basic using saturated aqueous NaHCO₃.The aqueous layer was extracted with methylene chloride (3×). Thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by flash columnchromatography (silica gel, 0%-100% solvent mixture B in methylenechloride; solvent mixture B=80:18:2 methylenechloride/methanol/concentrated ammonium hydroxide) to give the titlecompound (2.60 g, 36%) as a yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 7.29(t, J=8.0 Hz, 1H), 6.83 (d, J=7.0 Hz, 1H), 6.55 (d, J=8.5 Hz, 0.7H),6.41 (d, J=8.5 Hz, 0.3H), 3.20 (s, 3H), 3.17-2.94 (m, 7H), 2.80 (t,J=7.0 Hz, 0.6H), 2.73 (t, J=7.0 Hz, 1.4H), 1.89-1.85 (m, 3H), 1.74-1.60(m, 1H).

c)2-Bromo-10-methyl-7,8,9,10-tetrahydro-5H-6,9-ethanopyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine

A solution of(Z)-4-(2-(6-bromopyridin-2-yl)-2-methylhydrazono)-1-azabicyclo[3.2.2]nonane(2.40 g, 7.40 mmol) in phenylether (100 mL) was heated at 300° C. for 2h. After cooling to room temperature, the reaction mixture was dilutedwith ethyl acetate and washed with 1N HCl (3×). The aqueous layer wasmade basic with 6N NaOH and extracted with methylene chloride (3×). Thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by flash columnchromatography (silica gel, 0%-100% solvent mixture B in methylenechloride; solvent mixture B=80:18:2 methylenechloride/methanol/concentrated ammonium hydroxide) to give the titlecompound (275 mg, 12%) as a brown solid: ¹H NMR (500 MHz, CDCl₃) δ 6.93(d, J=7.5 Hz, 1H), 6.71 (d, J=7.5 Hz, 1H), 3.74 (s, 2H), 3.25-3.13 (m,5H), 3.10 (s, 3H), 2.01-1.85 (m, 4H).

d)4-(Benzyloxy)-1-(10-methyl-7,8,9,10-tetrahydro-5H-6,9-ethanopyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

2-Bromo-10-methyl-7,8,9,10-tetrahydro-5H-6,9-ethanopyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine(150 mg, 0.490 mmol), 4-benzyloxypyridone (108 mg, 0.530 mmol), Cs₂CO₃(176 mg, 0.540 mmol), 8-hydroxyquinoline (14.0 mg, 0.100 mmol), andcopper iodide (112 mg, 0.590 mmol) were suspended in DMSO (5 mL) anddegassed under reduced pressure for 45 min. The suspension was put undernitrogen and stirred at 135° C. for 18 h. After cooling to roomtemperature, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and theresulting suspension was stirred at 25° C. for 30 min. The suspensionwas passed through a plug of silica gel, and the filtrate was washedwith brine (3×). The filtrate was treated with activated carbon andNa₂SO₄, filtered through Celite and concentrated to dryness.Purification by semi preparative HPLC (Method B) gave the free base ofthe title compound as a white solid. 2 M HCl in Et₂O (1.00 mL, 2.00mmol) was added to a solution of the solid in MeOH (1 mL). Concentrationunder reduced pressure provided the title compound (22 mg, 10%) as apink solid: ¹H NMR (500 MHz, DMSO-d₆) δ 10.80 (br s, 1H), 7.77 (d, J=7.5Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.47-7.41 (m, 4H), 7.39-7.35 (m, 1H),6.99 (d, J=8.0 Hz, 1H), 6.13 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (d, J=2.5 Hz,1H), 5.15 (s, 2H), 4.66-4.64 (m, 1H), 4.08 (br s, 2H), 3.51-3.47 (m,4H), 3.10 (s, 3H), 2.41-2.35 (m, 2H), 2.10-2.07 (m, 2H); ESI MS m/z 427[M+H]⁺; HPLC (Method C) 94.8% (AUC), t_(R)=20.2 min.

Example 9 Preparation of4-(2,4-Difluorobenzyloxy)-1-(10-methyl-7,8,9,10-tetrahydro-5H-6,9-ethanopyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

a) 4-(2,4-Difluorobenzyloxy)pyridin-2(1H)-one (CAS Registry Number586373-58-2) (WO 2003/068230 to Devadas et al., which is herebyincorporated by reference in its entirety)

A suspension of (2,4-difluorophenyl)methanol (4.86 g, 33.7 mmol),2-chloro-4-iodopyridine (7.35 g, 30.7 mmol), Cs₂CO₃ (14.3 g, 43.8 mmol),CuI (5.83 g, 30.7 mmol) and 1,10-phenanthroline (1.11 g, 6.14 mmol) intoluene (20 mL) was degassed by bubbling N₂ through the suspension for15 min. The suspension was put under N₂, and heated at 105° C. for 18 h.The suspension was cooled, EtOAc (50 mL) was added, and the resultingsuspension was passed through a plug of SiO₂. The resulting solution wasconcentrated under reduced pressure. Flash chromatography on silica gel(hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. Asuspension of the white solid and NH₄OAc (8.21 g, 107 mmol) in 1:1HCO₂H/H₂O (40 mL) was heated at reflux with stirring for 4 d. Thesolution was cooled and concentrated under reduced pressure. Theresulting residue was made basic with saturated NaHCO₃ solution, and theresulting suspension was filtered. The solid was washed with H₂O anddried under reduced pressure to afford 3.16 g (44%) of the titlecompound as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.14 (br s, 1H),7.62 (br dd, J=15.3, 8.7 Hz, 1H), 7.33 (ddd, J=10.5, 10.5, 2.4 Hz, 1H),7.25 (d, J=7.2 Hz, 1H), 7.12 (ddd, J=8.4, 8.4, 1.8 Hz, 1H), 5.91-5.82(m, 2H), 5.06 (s, 2H).

b)4-(2,4-Difluorobenzyloxy)-1-(10-methyl-7,8,9,10-tetrahydro-5H-6,9-ethanopyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

2-Bromo-10-methyl-7,8,9,10-tetrahydro-5H-6,9-ethanopyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine(58 mg, 0.19 mmol), 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (45 mg,0.19 mmol), Cs₂CO₃ (176 mg, 0.380 mmol), 8-hydroxyquinoline (5.5 mg,0.040 mmol), and copper iodide (54 mg, 0.28 mmol) were suspended in DMSO(2.5 mL) and degassed under reduced pressure for 45 min. The suspensionwas put under nitrogen and stirred at 135° C. for 18 h. After cooling toroom temperature, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (5 mL) was added and theresulting suspension was stirred at 25° C. for 30 min. The suspensionwas passed through a plug of silica gel, and the filtrate was washedwith brine (3×). The filtrate was dried over Na₂SO₄ and concentrated todryness. Purification by flash column chromatography (reversed-phaseC18, 5%-80% acetonitrile with 0.05% formic acid in water with 0.05%formic acid) gave the free base of the title compound (20 mg) as a whitesolid. 1.25 M HCl in methanol (0.05 mL, 0.06 mmol) was added to asolution of the solid in MeOH (2 mL). Concentration under reducedpressure provided the title compound (18 mg, 19%) as an off-white solid:¹H NMR (500 MHz, CD₃OD) δ 7.99 (d, J=8.5 Hz, 1H), 7.81 (d, J=7.5 Hz,1H), 7.62-7.56 (m, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.08-7.02 (m, 2H), 6.30(dd, J=7.5, 2.5 Hz, 1H), 6.16 (d, J=2.5 Hz, 1H), 5.20 (s, 2H), 4.82 (brs, 2H), 3.85 (s, 3H), 3.72-3.65 (m, 3H), 3.55-3.48 (m, 2H), 2.48-2.41(m, 2H), 2.33-2.26 (m, 2H); ESI MS m/z 463 [M+H]⁺; HPLC (Method A) 98.7%(AUC), t_(R)=13.5 min.

Example 10 Preparation of1-(10-Methyl-7,8,9,10-tetrahydro-5H-6,9-ethanopyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-onehydrochloride

a) 4-(4-(Trifluoromethyl)phenyl)pyridine 1-oxide (CAS Registry Number545396-52-9) (WO 2003/049702 to Bo et al., which is hereby incorporatedby reference in its entirety)

4-Chloropyridine-N-oxide (3.0 g, 23 mmol),4-trifluoromethylphenylboronic acid (6.57 g, 34.6 mmol), K₂CO₃ (4.8 g,35 mmol) and PdCl₂(dppf) (470 mg, 0.57 mmol) were stirred in DMSO (40mL) under vacuum for 30 min. The flask was flushed with nitrogen, andthe mixture was heated to 80° C. for 10 min. Upon cooling, the mixturewas diluted with methylene chloride and washed with 5% lithium chloridesolution (5×), dried, concentrated, and the residue was purified byflash column chromatography (40 g ISCO column eluting with methylenechloride and a methanol/ammonia mixture (10:1); gradient 100% methylenechloride to 80% methylene chloride over 30 min at 40 mL/min) to providethe title compound (1.90 g, 34%) as a tan solid: ESI MS m/z 240 [M+H]⁺.

b) 4-(4-(Trifluoromethyl)phenyl)pyridin-2(1H)-one (CAS Registry Number942947-10-6) (U.S. Published Patent Application No. US 2007;149513 toChen et al., which is hereby incorporated by reference in its entirety)

4-(4-(Trifluoromethyl)phenyl)pyridine-1-oxide (1.9 g, 7.9 mmol) washeated to 140° C. in acetic anhydride (80 mL) for 5 h. The mixture wasconcentrated and then heated at 80° C. for 1 h in a mixture of MeOH (20mL) and aqueous 1 N NaOH (15 mL). The resulting black solution wasconcentrated to a volume of 15 mL, and the solid was filtered off,rinsed with CH₂Cl₂ and dried under vacuum to provide the title compound(1.26 g, 66%) as a brown solid: ¹H NMR (300 MHz, CD₃OD) δ 7.80-7.74 (brm, 5H), 6.85-6.66 (br m, 2H).

c)1-(10-Methyl-7,8,9,10-tetrahydro-5H-6,9-ethanopyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-onehydrochloride

2-Bromo-10-methyl-7,8,9,10-tetrahydro-5H-6,9-ethanopyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine(70 mg, 0.23 mmol), 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (52mg, 0.23 mmol), Cs₂CO₃ (150 mg, 0.46 mmol), 8-hydroxyquinoline (6.7 mg,0.050 mmol), and copper iodide (66 mg, 0.35 mmol) were suspended in DMSO(3 mL) and degassed under reduced pressure for 45 min. The suspensionwas put under nitrogen and stirred at 135° C. for 18 h. After cooling toroom temperature, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (6 mL) was added, and theresulting suspension was stirred at 25° C. for 30 min. The suspensionwas passed through a plug of silica gel and the filtrate was washed withbrine (3×). The filtrate was dried over Na₂SO₄ and concentrated todryness. Purification by flash column chromatography (reversed-phaseC18, 5%-90% acetonitrile with 0.05% formic acid in water with 0.05%formic acid) gave the free base of the title compound (16 mg) as ayellow solid. 1.25 M HCl in methanol (33 μL, 0.040 mmol) was added to asolution of the solid in MeOH (2 mL). Concentration under reducedpressure provided the title compound (18 mg, 16%) as a yellow solid: ¹HNMR (500 MHz, CD₃OD) δ 8.04-8.01 (m, 2H), 7.97 (d, J=8.0 Hz, 2H), 7.85(d, J=8.0 Hz, 2H), 7.47 (d, J=8.5 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 6.90(dd, J=7.0, 2.0 Hz, 1H), 4.84 (br s, 2H), 3.87 (s, 3H), 3.73-3.67 (m,3H), 3.56-3.50 (m, 2H), 2.49-2.42 (m, 2H), 2.35-2.30 (m, 2H); ESI MS m/z465 [M+H]⁺; HPLC (Method A) 95.0% (AUC), t_(R)=14.3 min.

Example 11 Preparation of4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-7,8,9,10-tetrahydro-5H-6,9-ethanopyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

2-Bromo-10-methyl-7,8,9,10-tetrahydro-5H-6,9-ethanopyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine(69.5 mg, 0.220 mmol),4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (50.0 mg, 0.220mmol), Cs₂CO₃ (143 mg, 0.440 mmol), 8-hydroxyquinoline (6.3 mg, 40μmol), and copper iodide (63.0 mg, 0.330 mmol) were suspended in DMSO (3mL) and degassed under reduced pressure for 45 min. The suspension wasput under nitrogen and stirred at 135° C. for 18 h. After cooling toroom temperature, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (6 mL) was added, and theresulting suspension was stirred at 25° C. for 30 min. The suspensionwas passed through a plug of silica gel, and the filtrate was washedwith brine (3×). The filtrate was treated with activated carbon andNa₂SO₄, filtered through Celite and concentrated to dryness.Purification by preparative thin layer chromatography (TLC) (silica gel,89:11:0.1 methylene chloride/methanol/concentrated ammonium hydroxide)gave the free base of the title compound as a yellow solid. 1.25 M HClin MeOH (30 μL, 38 μmol) was added to a solution of the solid in MeOH (1mL). Concentration under reduced pressure provided the title compound(9.8 mg, 9%) as a yellow solid: ¹H NMR (500 MHz, CD₃OD) δ 8.54 (d, J=2.5Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.77-7.68 (m,2H), 7.36 (d, J=8.5 Hz, 1H), 6.38 (dd, J=8.0, 2.5 Hz, 1H), 6.14 (d,J=2.5 Hz, 1H), 5.30 (s, 2H), 4.82 (br s, 2H), 3.84 (s, 3H), 3.71-3.64(m, 3H), 3.54-3.48 (m, 2H), 2.48-2.41 (m, 2H), 2.32-2.26 (m, 2H); ESI MSm/z 446 [M+H]⁺; HPLC (Method C) 94.4% (AUC), t_(R)=12.3 min.

Example 12 Preparation of Additional Compounds

In accordance with further embodiments of the invention, there areprovided the following compounds, which may be synthesized by analogy bythe methods shown and described above:

TABLE 1 Additional Compounds Synthesized by Analogous Methods NameStructure 4-(Benzyloxy)-1-(3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one

5-(Benzyloxy)-2-(6-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-8-yl)pyridazin-3(2H)-one

4-(Benzyloxy)-1-(3,4,5,6-tetrahydro-1H-2,5-methanoazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one

5-(Benzyloxy)-2-(6-methyl-3,4,5,6-tetrahydro-1H-2,5-methanoazepino[4,3-b]indol-8-yl)pyridazin-3(2H)-one

1-(6-Methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-8-yl)-4-phenethyl- piperazin-2-one

l-(6-Methyl-3,4,5,6-tetrahydro-1H-2,5-methanoazepino[4,3-b]indol-8-yl)-4- phenethylpiperazin-2-one

Example 13 Binding Assay for Human Melanin-Concentrating Hormone (McH₁)Receptor

Evaluation of the affinity of compounds for the human MCH-1 receptor wasaccomplished using4-(3,4,5-tritritiumbenzyloxy)-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)pyridin-2(1H)-oneand membranes prepared from stable CHO-K1 cells expressing the humanMCH-1 receptor obtained from Euroscreen (Batch 1138). Cell membranehomogenates (8.92 μg protein) were incubated for 60 min at 25° C. with1.4 nM of the [³H]-labeled compound in the absence or presence of thetest compound in 50 mM Tris-HCl buffer, pH 7.4. Nonspecific binding wasdetermined in the presence of 50 μM1-(5-(4-cyanophenyl)bicyclo[3.1.0]hexan-2-yl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-(4-methylpiperazin-1-yl)propyl)urea.Following incubation, the samples were filtered rapidly under vacuumthrough Skatron 11731 filters, pre-soaked in 0.5% polyethylenimine, andwashed with ice-cold 50 mM Tris-HCl buffer, pH 7.4, (wash setting 9,9,0)using a Skatron cell harvester. The filters were counted forradioactivity in a liquid scintillation counter (Tri-Carb 2100TR,Packard) using a scintillation cocktail (Ultima Gold MV, Perkin Elmer).

The results are expressed as a percent inhibition of the controlradioligand specific binding. The IC₅₀ value (concentration causing ahalf-maximal inhibition of control specific binding) and Hillcoefficient (n_(H)) were determined by non-linear regression analysis ofthe competition curve using Hill equation curve fitting. The inhibitionconstant (K_(i)) was calculated from the Cheng Prusoff equation:(K_(i)=IC₅₀/(1+(L/K_(D))), where L=concentration of radioligand in theassay, and K_(D)=affinity of the radioligand for the receptor.

By methods as described above, the compounds listed in Table 2 weresynthesized and tested for biological activity.

TABLE 2 Compounds Tested for Biological Activity Ex, MCH₁ Mass No.Structure K_(i) (nM) Spec ¹H NMR Data 2

6.4 412 ¹H NMR (500 MHz, CD₃OD) δ 7.57 (d, J = 7.5 Hz, 1H), 7.53 (d, J =8.4 Hz, 1H), 7.48-7.06 (m, 6H), 7.06 (dd, .J = 6.5, 1.8 Hz, 1H), 6.31(dd, J = 4.8, 2.7 Hz, 1H), 6.13 (d, J = 2.6 Hz, 1H), 5.18 (s, 2H),4.92-4.87 (m, 1H), 4.54 (d, J = 14.0, 1H), 3.94-3.92 (m, 2H), 3.81-3.77(m, 4H), 3.71 (dd, J = 7.0, 3.5 Hz, 1H), 3.44-3.42 (m, 1H), 2.57-2.51(m, 1H), 2.40-2.30 (m, 1H) 3

5.9 426 ¹H NMR (500 MHz, CD₃OD) δ 7.69 (d, J = 7.5 Hz, 1H), 7.54 (d, J =8.4 Hz, 1H), 7.49-7.36 (m, 5H), 7.08 (dd, J = 6.6, 1.7 Hz, 1H), 6.45(dd, J = 4.9, 2.7 Hz, 1H), 6.24 (d, J = 2.7 Hz, 1H), 5.23 (s, 2H), 4.79(s, 2H), 3.77-3.92 (s, 3H), 3.70- 3.60 (m, 4H), 3.52-3.47 (m, 2H), 2.46-2.40 (m, 2H), 2.27-2.26 (m, 2H) 4

44 445 ¹H NMR (500 MHz, CD₃OD) δ 8.57 (d, J = 2.5 Hz, 1H ), 7.81-7.77(m, 1H), 7.74-7.71 (m, 1H), 7.69 (d, J = 7.5 Hz, 1H ), 7.54 (d, J = 8.5Hz, 1H ), 7.49 (d, J = 2.0 Hz, 1H ), 7.07 (dd, J = 6.5, 2.0 Hz, 1H ),6.45 (dd, J = 5.0, 2.5 Hz, 1H), 6.23 (d, J = 2.5 Hz, 1H), 5.33 (s, 2H),4.79 (br s, 2H), 3.77 (s, 3H), 3.70-3.60 (m, 3H), 3.52-3.47 (m, 2H),2.46-2.43 (m, 2H), 2.30-2.20 (m, 2H) 5

23 466 ¹H NMR (500 MHz, CD₃OD) δ 8.54 (d, J = 9.0 Hz, 1H), 8.28 (d, J =8.5 Hz, 1H), 7.91 (d, J = 7.0 Hz, 1H), 7.60-7.57 (m, 2H), 7.44 (d, J =1.5 Hz, 1H), 7.34 (dd, J = 5.0, 2.0 Hz, 1H), 7.17 (dd, J = 6.5, 2.0 Hz,1H), 4.81 (br s, 2H), 3.80 (s, 3H), 3.71-3.62 (m, 3H), 3.54-3.49 (m,2H), 2.47-2.43 (m, 2H), 2.35-2.25 (m, 2H) 6

123 465 ¹H NMR (500 MHz, CD₃OD) δ 9.05 (d, J = 2.0 Hz, 1H), 8.29 (dd, J= 6.0, 2.0 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H),7.58-7.56 (m, 2H), 7.40 (d, J = 1.5 Hz, 1H), 7.26 (dd, J = 5.0, 2.0 Hz,1H), 7.16 (dd, J = 6.5, 2.0 Hz, 1H), 4.81 (br s, 2H), 3.80 (s, 3H),3.71-3.62 (m, 3H), 3.54-3.50 (m, 2H), 2.47-2.44 (m, 2H), 2.35-2.25 (m,2H) 7

11 495 ¹H NMR (500 MHz, CD₃OD) δ 8.85 (s, 1H), 8.18-8.16 (dd, J = 8.0,1.5 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.54(d, J = 8.5 Hz, 1H), 7.48 (d, J = 1.5 Hz, 1H), 7.08-7.05 (dd, J = 8.0,1.5 Hz, 1H), 6.40-6.37 (dd, J = 7.5, 3.0 Hz, 1H), 6.21 (d, J = 2.5 Hz,1H), 5.37 (s, 2H), 4.79 (br s, 2H), 3.77 (s, 3H), 3.70-3.64 (m, 2H),3.63-3.60 (m, 1H), 3.53-3.47 (m, 2H), 2.46-2.42 (m, 2H), 2.29-2.23 (m,2H) 8

29 427 ¹H NMR (500 MHz, DMSO-d₆) δ 10.80 (br s, 1H), 7.77 (d, J = 7.5Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.47-7.41 (m, 4H), 7.39-7.35 (m, 1H),6.99 (d, J = 8.0 Hz, 1H), 6.13 (dd, J = 7.5, 2.5 Hz, 1H), 5.96 (d, J =2.5 Hz, 1H), 5.15 (s, 2H), 4.66- 4.64 (m, 1H), 4.08 (br s, 2H),3.51-3.47 (m, 4H), 3.10 (s, 3H), 2.41-2.35 (m, 2H), 2.10-2.07 (m, 2H) 9

15 463 ¹H NMR (500 MHz, CD₃OD) δ 7.99 (d, J = 8.5 Hz, 1H), 7.81 (d, J =7.5 Hz, 1H), 7.62-7.56 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.08-7.02 (m,2H), 6.30 (dd, J = 7.5, 2.5 Hz, 1H), 6.16 (d, J = 2.5 Hz, 1H), 5.20 (s,2H), 4.82 (br s, 2H), 3.85 (s, 3H), 3.72-3.65 (m, 3H), 3.55-3.48 (m,2H), 2.48-2.41 (m, 2H), 2.33-2.26 (m, 2H) 10

15 465 ¹H NMR (500 MHz, CD₃OD) δ 8.04- 8.01 (m, 2H), 7.97 (d, J = 8.0Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.5 Hz, 1H), 6.96 (d, J= 2.0 Hz, 1H), 6.90 (dd, J = 7.0, 2.0 Hz, 1H), 4.84 (br s, 2H), 3.87 (s,3H), 3.73-3.67 (m, 3H), 3.56-3.50 (m, 2H), 2.49-2.42 (m, 2H), 2.35-2.30(m, 2H) 11

25 446 ¹H NMR (500 MHz, CD₃OD) δ 8.54 (d, J = 2.5 Hz, 1H), 7.99 (d, J =8.5 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.77-7.68 (m, 2H), 7.36 (d, J =8.5 Hz, 1H), 6.38 (dd, J = 8.0, 2.5 Hz, 1H), 6.14 (d, J = 2.5 Hz, 1H),5.30 (s, 2H), 4.82 (br s, 2H), 3.84 (s, 3H), 3.71-3.64 (m, 3H),3.54-3.48 (m, 2H), 2.48-2.41 (m, 2H), 2.32-2.26 (m, 2H)

As compounds that bind strongly to MCH-1, compounds of formula I areexpected to be effective in reducing obesity.

The present invention is not limited to the compounds found in the aboveexamples, and many other compounds falling within the scope of theinvention may also be prepared using the procedures set forth in theabove synthetic schemes. The preparation of additional compounds offormula (I) using these methods will be apparent to one of ordinaryskill in the chemical arts.

The invention has been described in detail with particular reference tosome embodiments thereof, but it will be understood by those skilled inthe art that variations and modifications can be effected within thespirit and scope of the invention.

1. A compound of formula I:

wherein R¹ is selected from the group consisting of H, —S(O)_(q)R⁵,—C(O)R⁵, —C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR⁷, —NR⁷R⁸, and phenyl which is optionally substituted 1-3 times withhalogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁷, or—NR⁷R⁸; R² is independently selected at each location from the groupconsisting of H, halogen, —OR⁴, —NR⁴R⁵, —NR⁴C(O)R⁵, —NR⁴C(O)₂R⁵,—NR⁵C(O)NR⁵R⁶, —S(O)_(q)R⁵, —CN, —C(O)R⁵, —C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1to 3 substituents independently selected at each occurrence thereof fromC₁-C₃ alkyl, halogen, —CN, —OR⁷, —NR⁷R⁸, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR⁷, or —NR⁷R⁸; R³ is selected from the group consistingof H, halogen, —OR⁴, —NR⁴R⁵, —NR⁴C(O)R⁵, —NR⁴C(O)₂R⁵, —NR⁵C(O)NR⁵R⁶,—S(O)_(q)R⁵, —CN, —C(O)R⁵, —C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl,and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl,and heteroaryl is optionally substituted with from 1 to 3 substituentsindependently selected at each occurrence thereof from C₁-C₃ alkyl,halogen, —CN, —OR⁷, —NR⁷R⁸, and phenyl which is optionally substituted1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN,—OR⁷, or —NR⁷R⁸; R⁴ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R⁶, phenyl,or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy; R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, or benzyl, wherein phenyl orbenzyl is optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy; R⁶ is C₁-C₄ alkyl, C₁-C₄haloalkyl, or phenyl; R⁷ and R⁸ are each independently H, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R⁶, phenyl, or benzyl, wherein phenyl or benzyl isoptionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy; R⁹ isselected from the group consisting of H, halogen, —OR⁴, —NR⁴R⁵,—NR⁴C(O)R⁵, —NR⁴C(O)₂R⁵, —NR⁵C(O)NR⁵R⁶, —S(O)_(q)R⁵, —CN, —C(O)R⁵,—C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein eachof C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR⁷, —NR⁷R⁸, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁷, or —NR⁷R⁸; X is CR⁹,C(R⁹)₂, N, or—NR⁹; Y is CR⁹, C, or N; Z is C, CH, or N; L is—(CH₂)_(p)—O—, —(CH₂)_(p)—, —CH═CH—, or a bond; B is aryl, heteroaryl,heterocyclyl, or cycloalkyl, wherein each of the aryl, heteroaryl,heterocyclyl, or cycloalkyl is optionally substituted with from 1 to 3substituents selected from the group consisting of H, alkoxy, —S-alkyl,optionally substituted C₁-C₆ alkyl, halogen, —CF₃, and —CN; n is 1 or 2;m is 0, 1, 2, or 3; p is from 1 to 4; q is from 0 to 2; and

represents an optional double bond, or an oxide thereof, apharmaceutically acceptable salt thereof, a solvate thereof, or prodrugthereof.
 2. The compound according to claim 1, wherein the compound hasthe structure


3. The compound according to claim 1, wherein the compound has thestructure


4. The compound according to claim 3, wherein the compound has thestructure


5. The compound according to claim 3, wherein the compound is selectedfrom the group consisting of:


6. The compound according to claim 1, wherein the compound has thestructure:


7. The compound according to claim 6, wherein the compound is selectedfrom the group consisting of


8. The compound according to claim 6, wherein the compound is selectedfrom the group consisting of


9. The compound according to claim 6, wherein the compound is selectedfrom the group consisting of


10. The compound according to claim 1, wherein X is CH.
 11. The compoundaccording to claim 1, wherein X is N.
 12. The compound according toclaim 1, wherein L is a bond.
 13. The compound according to claim 1,wherein L is —CH₂—O—.
 14. The compound according to claim 1, wherein Bis aryl.
 15. The compound according to claim 14, wherein B is phenyl.16. The compound according to claim 1, wherein B is heteroaryl.
 17. Thecompound according to claim 16, wherein B is pyridinyl.
 18. The compoundaccording to claim 17, wherein B is pyridin-2-yl.
 19. The compoundaccording to claim 17, wherein B is pyridin-3-yl.
 20. The compoundaccording to claim 16, wherein B is pyridazinyl.
 21. The compoundaccording to claim 20, wherein B is pyridazin-3-yl.
 20. The compoundaccording to claim 1, wherein B is unsubstituted.
 22. The compoundaccording to claim 1, wherein B is substituted with at least onesubstituent selected from the group consisting of trifluoromethyl andfluoro.
 24. The compound according to claim 1, wherein B is selectedfrom the group consisting of phenyl, 5-(trifluoromethyl)pyridin-2-yl,5-fluoropyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl,6-(trifluoromethyl)pyridazin-3-yl, 2,4-difluorophenyl, and4-(trifluoromethyl)phenyl.
 25. A compound according to claim 1, whereinR¹ is H.
 26. A compound according to claim 1, wherein R¹ is alkyl. 27.The compound according to claim 1, wherein the compound is an HCl salt.28. A pharmaceutical composition comprising a therapeutically effectiveamount of the compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 29. A method of treating a disease or conditionwhich is susceptible to treatment with a MCH-1 receptor antagonistcomprising: selecting a patient with a disease or condition which issusceptible to treatment with a MCH-1 antagonist, and administering tothe patient a therapeutically effective amount of a compound of claim 1or a pharmaceutically acceptable salt thereof.
 30. The method accordingto claim 29, wherein the disease or condition is selected from the groupconsisting of obesity, general anxiety disorders, social phobias,vertigo, obsessive-compulsive disorders, panic disorders, post-traumaticstress disorders, Parkinson's Disease Psychosis, schizophrenia,cognitive decline and defects in schizophrenia, presenile dementias,Alzheimer's Disease, psychological disorders, depression, substanceabuse disorders, dementia associated with neurodegenerative disease,cognition deficits, and epilepsy.
 31. The method according to claim 29further comprising: administering to the patient a therapeuticallyeffective amount of a therapeutic adjunct.
 32. The method according toclaim 31, wherein the therapeutic adjunct is selected from the groupconsisting of phenylpropanolamine, ephedrine, pseudoephedrine,phentermine, a cholecystokinin-A agonist, a monoamine reuptakeinhibitor, a sympathomimetic agent, a serotonergic agent, a dopamineagonist, a melanocyte-stimulating hormone receptor agonist or mimetic, amelanocyte-stimulating hormone analog, a cannabinoid receptor antagonistor inverse agonist, a melanin concentrating hormone receptor antagonist,a serotonin 5-HT₆ receptor antagonist, a serotonin 5-HT_(2C) receptoragonist, leptin, a leptin analog, a leptin receptor agonist, amylinpeptide, an amylin analog, an amylin receptor agonist, a neuropeptide Yreceptor modulator, a galanin antagonist, a GI lipase inhibitor ordecreaser, a bombesin agonist, dehydroepiandrosterone or analogsthereof, a glucocorticoid receptor agonist, a glucocorticoid receptorantagonist, an orexin receptor antagonist, an urocortin binding proteinantagonist, an agonist of the glucagon-like peptide-1 receptor, aciliary neurotrophic factor, an allosteric modulator of the GABA_(A)receptor, a serotonin 5-HT_(1A) receptor partial agonist, a selectiveserotonin reuptake inhibitor, a serotonin-norepinephrine reuptakeinhibitor, a monoamine neurotransmitter reuptake inhibitor of tricyclicantidepressant class, a combined serotonin reuptake inhibitor and5-HT_(2C) antagonist, an H₁ receptor antagonist, a noradrenergic andspecific serotonergic antidepressant, a norepinephrine reuptakeinhibitor, a norepinephrine-dopamine reuptake inhibitor, a monoamineoxidase inhibitor, an AMP-activated protein kinase agonist, a peroxisomeproliferator-activated receptor gamma activator, a HMG-CoA reductaseinhibitor, a PDE4 inhibitor, and combinations thereof.
 33. A method oftreating obesity in a subject in need of weight loss comprising:selecting a patient in need of weight loss, and administering to thepatient a therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 34. The method according toclaim 33 further comprising: administering to the patient atherapeutically effective amount of an anti-obesity adjunct.
 35. Themethod according to claim 34, wherein the anti-obesity adjunct isselected from the group consisting of phenylpropanolamine, ephedrine,pseudoephedrine, phentermine, a cholecystokinin-A agonist, a monoaminereuptake inhibitor, a sympathomimetic agent, a serotonergic agent, adopamine agonist, a melanocyte-stimulating hormone receptor agonist ormimetic, a melanocyte-stimulating hormone analog, a cannabinoid receptorantagonist or inverse agonist, a melanin concentrating hormone receptorantagonist, a serotonin 5-HT₆ receptor antagonist, a serotonin 5-HT_(2C)receptor agonist, leptin, a leptin analog, a leptin receptor agonist,amylin peptide, an amylin analog, an amylin receptor agonist, aneuropeptide Y receptor modulator, a galanin antagonist, a GI lipaseinhibitor or decreaser, a bombesin agonist, dehydroepiandrosterone oranalogs thereof, a glucocorticoid receptor agonist, a glucocorticoidreceptor antagonist, an orexin receptor antagonist, an urocortin bindingprotein antagonist, an agonist of the glucagon-like peptide-1 receptor,a ciliary neurotrophic factor, and combinations thereof.
 36. A method oftreating obesity in a subject who has experienced weight losscomprising: selecting a patient who has experienced weight loss, andadministering to the patient a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof.
 37. Amethod of treating anxiety comprising: selecting a patient with anxiety,and administering to the patient a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof. 38.The method according to claim 37 further comprising: administering tothe patient a therapeutically effective amount of a anti-anxietyadjunct.
 39. The method according to claim 38, wherein the anti-anxietyadjunct is selected from the group consisting of an allosteric modulatorof the GABA_(A) receptor, a serotonin 5-HT_(1A) receptor partialagonist, a selective serotonin reuptake inhibitor, aserotonin-norepinephrine reuptake inhibitor, a monoamineneurotransmitter reuptake inhibitor of tricyclic antidepressant class, acombined serotonin reuptake inhibitor and 5-HT_(2C) antagonist, an H₁receptor antagonist, and combinations thereof.
 40. A method of treatingdepression comprising: selecting a patient with depression, andadministering to the patient a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof. 41.The method according to claim 38 further comprising: administering tothe patient a therapeutically effective amount of an anti-depressionadjunct.
 42. The method according to claim 41, wherein theanti-depression adjunct is selected from the group consisting of aserotonin 5-HT_(1A) receptor partial agonist, a selective serotoninreuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, amonoamine neurotransmitter reuptake inhibitor of tricyclicantidepressant class, a combined serotonin reuptake inhibitor and5-HT_(2C) antagonist, a noradrenergic and specific serotonergicantidepressant, a norepinephrine reuptake inhibitor, anorepinephrine-dopamine reuptake inhibitor, a monoamine oxidaseinhibitor, and combinations thereof.
 42. A method of treatingnon-alcoholic fatty liver disease comprising: selecting a patient whohas non-alcoholic fatty liver disease, and administering to the patienta therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 44. The method according toclaim 41 further comprising: administering to the patient atherapeutically effective amount of an anti-non-alcoholic fatty liverdisease adjunct.
 45. The method according to claim 44, wherein theanti-non-alcoholic fatty liver disease adjunct is selected from thegroup consisting of an AMP-activated protein kinase agonist, aperoxisome proliferator-activated receptor gamma activator, a HMG-CoAreductase inhibitor, a PDE4 inhibitor, and combinations thereof.
 46. Aprocess for preparation of a product compound of formula I:

wherein: R¹ is selected from the group consisting of H, halogen, —OR⁴,—NR⁴R⁵, —NR⁴C(O)R⁵, —NR⁴C(O)₂R⁵, —NR⁴C(O)NR⁵R⁶, —S(O)_(q)R⁵, —CN,—C(O)R⁵, —C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR⁷, —NR⁷R⁸, and phenyl which is optionally substituted 1-3 times withhalogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁷, or—NR⁷R⁸; R² is independently selected at each location from the groupconsisting of H, halogen, —OR⁴, —NR⁴R⁵, —NR⁴C(O)R⁵, —NR⁴C(O)₂R⁵,—NR⁵C(O)NR⁵R⁶, —S(O)_(q)R⁵, —CN, —C(O)R⁵, —C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1to 3 substituents independently selected at each occurrence thereof fromC₁-C₃ alkyl, halogen, —CN, —OR⁷, —NR⁷R⁸, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR⁷, or —NR⁷R⁸; R³ is selected from the group consistingof H, halogen, —OR⁴, —NR⁴R⁵, —NR⁴C(O)R⁵, —NR⁴C(O)₂R⁵, —NR⁵C(O)NR⁵R⁶,—S(O)_(q)R⁵, —CN, —C(O)R⁵, —C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl,and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl,and heteroaryl is optionally substituted with from 1 to 3 substituentsindependently selected at each occurrence thereof from C₁-C₃ alkyl,halogen, —CN, —OR⁷, —NR⁷R⁸, and phenyl which is optionally substituted1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN,—OR⁷, or —NR⁷R⁸; R⁴ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R⁶, phenyl,or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy; R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, or benzyl, wherein phenyl orbenzyl is optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy; R⁶ is C₁-C₄ alkyl, C₁-C₄haloalkyl, or phenyl; R⁷ and R⁸ are each independently H, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R⁶, phenyl, or benzyl, wherein phenyl or benzyl isoptionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy; R⁹ isselected from the group consisting of H, halogen, —OR⁴, —NR⁴R⁵,—NR⁴C(O)R⁵, —NR⁴C(O)₂R⁵, —NR⁵C(O)NR⁵R⁶, —S(O)_(q)R⁵, —CN, —C(O)R⁵,—C(O)NR⁴R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein eachof C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR⁷, —NR⁷R⁸, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁷, or —NR⁷R⁸; X is CR⁹,C(R⁹)₂, N, or—NR⁹; Y is CR⁹, C, or N; Z is C, CH, or N; L is —CH₂—O—,—(CH₂)_(p)—, —CH═CH—, or a bond; B is aryl, heteroaryl, heterocycyl, orcycloalkyl, wherein each of the aryl, heteroaryl, heterocycyl, orcycloalkyl is optionally substituted with from 1 to 3 substituentsselected from the group consisting of H, alkoxy, —S-alkyl, optionallysubstituted C₁-C₆ alkyl, halogen, —CF₃, and —CN; n is 1 or 2; m is 0, 1,2, or 3; p is from 1 to 4; q is from 0 to 2; and

represents an optional double bond, said process comprising: treating afirst intermediate compound of formula II:

wherein Q is a halogen, under conditions effective to form the productcompound.
 47. The process according to claim 46 further comprising:reacting a compound of formula III:

with a compound of formula IV:

under conditions effective to produce the first intermediate compound.